RBCC

Full text data of BBS1

BBS1 (BBS2L2) [Confidence: low (only semi-automatic identification from reviews)]
Bardet-Biedl syndrome 1 protein (BBS2-like protein 2)

UniProt Q8NFJ9
ID BBS1_HUMAN Reviewed; 593 AA.
AC Q8NFJ9; Q32MN0; Q96SN4;
DT 07-NOV-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2002, sequence version 1.
DT 22-JAN-2014, entry version 91.
DE RecName: Full=Bardet-Biedl syndrome 1 protein;
DE AltName: Full=BBS2-like protein 2;
GN Name=BBS1; Synonyms=BBS2L2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT BBS1 ARG-390.
RX PubMed=12118255; DOI=10.1038/ng935;
RA Mykytyn K., Nishimura D.Y., Searby C.C., Shastri M., Yen H.,
RA Beck J.S., Braun T., Streb L.M., Cornier A.S., Cox G.F., Fulton A.B.,
RA Carmi R., Lueleci G., Chandrasekharappa S.C., Collins F.S.,
RA Jacobson S.G., Heckenlively J.R., Weleber R.G., Stone E.M.,
RA Sheffield V.C.;
RT "Identification of the gene (BBS1) most commonly involved in Bardet-
RT Biedl syndrome, a complex human obesity syndrome.";
RL Nat. Genet. 31:435-438(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP INTERACTION WITH CCDC28B.
RX PubMed=16327777; DOI=10.1038/nature04370;
RA Badano J.L., Leitch C.C., Ansley S.J., May-Simera H., Lawson S.,
RA Lewis R.A., Beales P.L., Dietz H.C., Fisher S., Katsanis N.;
RT "Dissection of epistasis in oligogenic Bardet-Biedl syndrome.";
RL Nature 439:326-330(2006).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY, SUBUNIT, FUNCTION, SUBCELLULAR
RP LOCATION, AND INTERACTION WITH RAB3IP.
RX PubMed=17574030; DOI=10.1016/j.cell.2007.03.053;
RA Nachury M.V., Loktev A.V., Zhang Q., Westlake C.J., Peraenen J.,
RA Merdes A., Slusarski D.C., Scheller R.H., Bazan J.F., Sheffield V.C.,
RA Jackson P.K.;
RT "A core complex of BBS proteins cooperates with the GTPase Rab8 to
RT promote ciliary membrane biogenesis.";
RL Cell 129:1201-1213(2007).
RN [6]
RP INTERACTION WITH ALDOB.
RX PubMed=18000879; DOI=10.1002/cm.20250;
RA Oeffner F., Moch C., Neundorf A., Hofmann J., Koch M., Grzeschik K.H.;
RT "Novel interaction partners of Bardet-Biedl syndrome proteins.";
RL Cell Motil. Cytoskeleton 65:143-155(2008).
RN [7]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [8]
RP FUNCTION, FUNCTION OF THE BBSOME COMPLEX, IDENTIFICATION IN THE BBSOME
RP COMPLEX, AND SUBCELLULAR LOCATION.
RX PubMed=22072986; DOI=10.1371/journal.pgen.1002358;
RA Seo S., Zhang Q., Bugge K., Breslow D.K., Searby C.C., Nachury M.V.,
RA Sheffield V.C.;
RT "A novel protein LZTFL1 regulates ciliary trafficking of the BBSome
RT and Smoothened.";
RL PLoS Genet. 7:E1002358-E1002358(2011).
RN [9]
RP VARIANTS BBS1 200-ILE-THR-201 DEL; ARG-390 AND PRO-518.
RX PubMed=12524598; DOI=10.1086/346172;
RA Mykytyn K., Nishimura D.Y., Searby C.C., Beck G., Bugge K.,
RA Haines H.L., Cornier A.S., Cox G.F., Fulton A.B., Carmi R.,
RA Iannaccone A., Jacobson S.G., Weleber R.G., Wright A.F., Riise R.,
RA Hennekam R.C.M., Lueleci G., Berker-Karauzum S., Biesecker L.G.,
RA Stone E.M., Sheffield V.C.;
RT "Evaluation of complex inheritance involving the most common Bardet-
RT Biedl syndrome locus (BBS1).";
RL Am. J. Hum. Genet. 72:429-437(2003).
RN [10]
RP VARIANT BBS1 LYS-234.
RX PubMed=12567324; DOI=10.1086/368204;
RA Badano J.L., Ansley S.J., Leitch C.C., Lewis R.A., Lupski J.R.,
RA Katsanis N.;
RT "Identification of a novel Bardet-Biedl syndrome protein, BBS7, that
RT shares structural features with BBS1 and BBS2.";
RL Am. J. Hum. Genet. 72:650-658(2003).
RN [11]
RP VARIANTS BBS1 ARG-35; GLU-53; ASN-148; LYS-234; SER-305; ILE-389 DEL;
RP ARG-390; SER-434 HIS-503 AND GLN-518.
RX PubMed=12677556; DOI=10.1086/375178;
RA Beales P.L., Badano J.L., Ross A.J., Ansley S.J., Hoskins B.E.,
RA Kirsten B., Mein C.A., Froguel P., Scambler P.J., Lewis R.A.,
RA Lupski J.R., Katsanis N.;
RT "Genetic interaction of BBS1 mutations with alleles at other BBS loci
RT can result in non-Mendelian Bardet-Biedl syndrome.";
RL Am. J. Hum. Genet. 72:1187-1199(2003).
RN [12]
RP VARIANTS BBS1 ARG-390 AND PRO-518.
RX PubMed=12920096; DOI=10.1136/jmg.40.8.e104;
RA Fauser S., Munz M., Besch D.;
RT "Further support for digenic inheritance in Bardet-Biedl syndrome.";
RL J. Med. Genet. 40:E104-E104(2003).
RN [13]
RP VARIANTS BBS1 GLN-160 AND ARG-390.
RX PubMed=15770229; DOI=10.1038/sj.ejhg.5201372;
RA Hichri H., Stoetzel C., Laurier V., Caron S., Sigaudy S., Sarda P.,
RA Hamel C., Martin-Coignard D., Gilles M., Leheup B., Holder M.,
RA Kaplan J., Bitoun P., Lacombe D., Verloes A., Bonneau D.,
RA Perrin-Schmitt F., Brandt C., Besancon A.-F., Mandel J.-L., Cossee M.,
RA Dollfus H.;
RT "Testing for triallelism: analysis of six BBS genes in a Bardet-Biedl
RT syndrome family cohort.";
RL Eur. J. Hum. Genet. 13:607-616(2005).
RN [14]
RP VARIANTS VAL-206 AND LEU-245, AND VARIANT BBS1 ARG-390.
RX PubMed=21052717; DOI=10.1007/s00439-010-0902-8;
RA Janssen S., Ramaswami G., Davis E.E., Hurd T., Airik R.,
RA Kasanuki J.M., Van Der Kraak L., Allen S.J., Beales P.L., Katsanis N.,
RA Otto E.A., Hildebrandt F.;
RT "Mutation analysis in Bardet-Biedl syndrome by DNA pooling and
RT massively parallel resequencing in 105 individuals.";
RL Hum. Genet. 129:79-90(2011).
RN [15]
RP VARIANT ASP-559, AND INVOLVEMENT IN CILIOPATHIES.
RX PubMed=21258341; DOI=10.1038/ng.756;
RA Davis E.E., Zhang Q., Liu Q., Diplas B.H., Davey L.M., Hartley J.,
RA Stoetzel C., Szymanska K., Ramaswami G., Logan C.V., Muzny D.M.,
RA Young A.C., Wheeler D.A., Cruz P., Morgan M., Lewis L.R.,
RA Cherukuri P., Maskeri B., Hansen N.F., Mullikin J.C., Blakesley R.W.,
RA Bouffard G.G., Gyapay G., Rieger S., Tonshoff B., Kern I.,
RA Soliman N.A., Neuhaus T.J., Swoboda K.J., Kayserili H.,
RA Gallagher T.E., Lewis R.A., Bergmann C., Otto E.A., Saunier S.,
RA Scambler P.J., Beales P.L., Gleeson J.G., Maher E.R., Attie-Bitach T.,
RA Dollfus H., Johnson C.A., Green E.D., Gibbs R.A., Hildebrandt F.,
RA Pierce E.A., Katsanis N.;
RT "TTC21B contributes both causal and modifying alleles across the
RT ciliopathy spectrum.";
RL Nat. Genet. 43:189-196(2011).
RN [16]
RP VARIANTS BBS1 GLN-160; THR-330; ARG-390 AND ASN-524 DEL.
RX PubMed=21344540; DOI=10.1002/humu.21480;
RA Deveault C., Billingsley G., Duncan J.L., Bin J., Theal R.,
RA Vincent A., Fieggen K.J., Gerth C., Noordeh N., Traboulsi E.I.,
RA Fishman G.A., Chitayat D., Knueppel T., Millan J.M., Munier F.L.,
RA Kennedy D., Jacobson S.G., Innes A.M., Mitchell G.A., Boycott K.,
RA Heon E.;
RT "BBS genotype-phenotype assessment of a multiethnic patient cohort
RT calls for a revision of the disease definition.";
RL Hum. Mutat. 32:610-619(2011).
CC -!- FUNCTION: The BBSome complex is thought to function as a coat
CC complex required for sorting of specific membrane proteins to the
CC primary cilia. The BBSome complex is required for ciliogenesis but
CC is dispensable for centriolar satellite function. This ciliogenic
CC function is mediated in part by the Rab8 GDP/GTP exchange factor,
CC which localizes to the basal body and contacts the BBSome.
CC Rab8(GTP) enters the primary cilium and promotes extension of the
CC ciliary membrane. Firstly the BBSome associates with the ciliary
CC membrane and binds to RAB3IP/Rabin8, the guanosyl exchange factor
CC (GEF) for Rab8 and then the Rab8-GTP localizes to the cilium and
CC promotes docking and fusion of carrier vesicles to the base of the
CC ciliary membrane. The BBSome complex, together with the LTZL1,
CC controls SMO ciliary trafficking and contributes to the sonic
CC hedgehog (SHH) pathway regulation. Required for proper BBSome
CC complex assembly and its ciliary localization.
CC -!- SUBUNIT: Part of BBSome complex, that contains BBS1, BBS2, BBS4,
CC BBS5, BBS7, BBS8/TTC8, BBS9 and BBIP10. Interacts with the C-
CC terminus of RAB3IP. Interacts with CCDC28B and ALDOB.
CC -!- INTERACTION:
CC P05062:ALDOB; NbExp=4; IntAct=EBI-1805484, EBI-1045507;
CC Q9H0F7:ARL6; NbExp=4; IntAct=EBI-1805484, EBI-2891949;
CC Q9BXC9:BBS2; NbExp=6; IntAct=EBI-1805484, EBI-748297;
CC Q96RK4:BBS4; NbExp=5; IntAct=EBI-1805484, EBI-1805814;
CC Q8IWZ6:BBS7; NbExp=6; IntAct=EBI-1805484, EBI-1806001;
CC Q3SYG4:BBS9; NbExp=6; IntAct=EBI-1805484, EBI-2826852;
CC P68104:EEF1A1; NbExp=3; IntAct=EBI-1805484, EBI-352162;
CC P48356-1:Lepr (xeno); NbExp=3; IntAct=EBI-1805484, EBI-6143588;
CC Q15154:PCM1; NbExp=2; IntAct=EBI-1805484, EBI-741421;
CC Q96QF0-1:RAB3IP; NbExp=2; IntAct=EBI-1805484, EBI-747860;
CC -!- SUBCELLULAR LOCATION: Cell projection, cilium membrane. Cytoplasm.
CC Cytoplasm, cytoskeleton, microtubule organizing center,
CC centrosome, centriolar satellite.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8NFJ9-1; Sequence=Displayed;
CC Name=3; Synonyms=DPP3-BBS1;
CC IsoId=Q8NFJ9-2; Sequence=VSP_008854;
CC Note=Based on a readthrough transcript which may produce a
CC DPP3-BBS1 fusion protein. No experimental confirmation
CC available;
CC -!- TISSUE SPECIFICITY: Highly expressed in the kidney. Also found in
CC fetal tissue, testis, retina, adipose tissue, heart, skeletal
CC muscle and pancreas.
CC -!- DISEASE: Note=Ciliary dysfunction leads to a broad spectrum of
CC disorders, collectively termed ciliopathies. Overlapping clinical
CC features include retinal degeneration, renal cystic disease,
CC skeletal abnormalities, fibrosis of various organ, and a complex
CC range of anatomical and functional defects of the central and
CC peripheral nervous system. The ciliopathy range of diseases
CC includes Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert
CC syndrome, nephronophtisis, Senior-Loken syndrome, and Jeune
CC asphyxiating thoracic dystrophy among others. Single-locus
CC allelism is insufficient to explain the variable penetrance and
CC expressivity of such disorders, leading to the suggestion that
CC variations across multiple sites of the ciliary proteome,
CC including BBS1, influence the clinical outcome.
CC -!- DISEASE: Bardet-Biedl syndrome 1 (BBS1) [MIM:209900]: A syndrome
CC characterized by usually severe pigmentary retinopathy, early-
CC onset obesity, polydactyly, hypogenitalism, renal malformation and
CC mental retardation. Secondary features include diabetes mellitus,
CC hypertension and congenital heart disease. Bardet-Biedl syndrome
CC inheritance is autosomal recessive, but three mutated alleles (two
CC at one locus, and a third at a second locus) may be required for
CC clinical manifestation of some forms of the disease. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- WEB RESOURCE: Name=Mutations of the BBS1 gene; Note=Retina
CC International's Scientific Newsletter;
CC URL="http://www.retina-international.org/files/sci-news/bbs1mut.htm";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/BBS1";
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DR EMBL; AF503941; AAM92770.1; -; mRNA.
DR EMBL; AK027645; BAB55261.1; -; mRNA.
DR EMBL; BC109064; AAI09065.1; -; mRNA.
DR RefSeq; NP_078925.3; NM_024649.4.
DR UniGene; Hs.502915; -.
DR ProteinModelPortal; Q8NFJ9; -.
DR SMR; Q8NFJ9; 217-243, 299-324.
DR DIP; DIP-46564N; -.
DR IntAct; Q8NFJ9; 30.
DR STRING; 9606.ENSP00000353701; -.
DR PhosphoSite; Q8NFJ9; -.
DR DMDM; 38257662; -.
DR PaxDb; Q8NFJ9; -.
DR PRIDE; Q8NFJ9; -.
DR Ensembl; ENST00000318312; ENSP00000317469; ENSG00000174483.
DR GeneID; 582; -.
DR KEGG; hsa:582; -.
DR UCSC; uc001oij.1; human.
DR CTD; 582; -.
DR GeneCards; GC11P066276; -.
DR HGNC; HGNC:966; BBS1.
DR MIM; 209900; phenotype.
DR MIM; 209901; gene.
DR neXtProt; NX_Q8NFJ9; -.
DR Orphanet; 110; Bardet-Biedl syndrome.
DR PharmGKB; PA25275; -.
DR eggNOG; NOG84787; -.
DR HOGENOM; HOG000260890; -.
DR HOVERGEN; HBG045407; -.
DR InParanoid; Q8NFJ9; -.
DR KO; K16746; -.
DR OMA; LTAHINM; -.
DR GeneWiki; BBS1; -.
DR GenomeRNAi; 582; -.
DR NextBio; 2383; -.
DR PRO; PR:Q8NFJ9; -.
DR ArrayExpress; Q8NFJ9; -.
DR Bgee; Q8NFJ9; -.
DR CleanEx; HS_BBS1; -.
DR Genevestigator; Q8NFJ9; -.
DR GO; GO:0034464; C:BBSome; IDA:BHF-UCL.
DR GO; GO:0060170; C:cilium membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005815; C:microtubule organizing center; IEA:UniProtKB-SubCell.
DR GO; GO:0043001; P:Golgi to plasma membrane protein transport; IMP:MGI.
DR GO; GO:0035058; P:nonmotile primary cilium assembly; IMP:BHF-UCL.
DR GO; GO:0045494; P:photoreceptor cell maintenance; IMP:BHF-UCL.
DR GO; GO:0050896; P:response to stimulus; IEA:UniProtKB-KW.
DR GO; GO:0007601; P:visual perception; IEA:UniProtKB-KW.
DR InterPro; IPR011047; Quinonprotein_ADH-like_supfam.
DR SUPFAM; SSF50998; SSF50998; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Bardet-Biedl syndrome;
KW Cell membrane; Cell projection; Ciliopathy; Cilium;
KW Cilium biogenesis/degradation; Complete proteome; Cytoplasm;
KW Cytoskeleton; Disease mutation; Membrane; Mental retardation; Obesity;
KW Polymorphism; Protein transport; Reference proteome;
KW Sensory transduction; Transport; Vision.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 593 Bardet-Biedl syndrome 1 protein.
FT /FTId=PRO_0000064841.
FT MOD_RES 2 2 N-acetylalanine.
FT VAR_SEQ 1 16 MAAASSSDSDACGAES -> MDPSWRRSSHSWPQPMPDSGR
FT APVRPHLAKLEEDVWPCPQFHQTKAASGPPFV (in
FT isoform 3).
FT /FTId=VSP_008854.
FT VARIANT 35 35 H -> R (in BBS1).
FT /FTId=VAR_038880.
FT VARIANT 53 53 K -> E (in BBS1).
FT /FTId=VAR_038881.
FT VARIANT 148 148 D -> N (in BBS1; dbSNP:rs200688985).
FT /FTId=VAR_038882.
FT VARIANT 160 160 R -> Q (in BBS1).
FT /FTId=VAR_038883.
FT VARIANT 200 201 Missing (in BBS1).
FT /FTId=VAR_017214.
FT VARIANT 206 206 L -> V (in a patient with Bardet-Biedl
FT syndrome; dbSNP:rs146052054).
FT /FTId=VAR_066485.
FT VARIANT 234 234 E -> K (in BBS1; dbSNP:rs35520756).
FT /FTId=VAR_017215.
FT VARIANT 245 245 P -> L (in a patient with Bardet-Biedl
FT syndrome).
FT /FTId=VAR_066486.
FT VARIANT 305 305 G -> S (in BBS1).
FT /FTId=VAR_038884.
FT VARIANT 330 330 I -> T (in BBS1).
FT /FTId=VAR_066278.
FT VARIANT 389 389 Missing (in BBS1).
FT /FTId=VAR_038885.
FT VARIANT 390 390 M -> R (in BBS1; dbSNP:rs113624356).
FT /FTId=VAR_017216.
FT VARIANT 434 434 Y -> S (in BBS1).
FT /FTId=VAR_038886.
FT VARIANT 503 503 L -> H (in BBS1).
FT /FTId=VAR_038887.
FT VARIANT 518 518 L -> P (in BBS1).
FT /FTId=VAR_017217.
FT VARIANT 518 518 L -> Q (in BBS1).
FT /FTId=VAR_038888.
FT VARIANT 524 524 Missing (in BBS1).
FT /FTId=VAR_066279.
FT VARIANT 559 559 G -> D (in a patient with Meckel-Gruber
FT like syndrome also carrying L-753 in
FT TTC21B and a variant in CC2D2A).
FT /FTId=VAR_065554.
SQ SEQUENCE 593 AA; 65083 MW; 94C0C05667FE582D CRC64;
MAAASSSDSD ACGAESNEAN SKWLDAHYDP MANIHTFSAC LALADLHGDG EYKLVVGDLG
PGGQQPRLKV LKGPLVMTES PLPALPAAAA TFLMEQHEPR TPALALASGP CVYVYKNLRP
YFKFSLPQLP PNPLEQDLWN QAKEDRIDPL TLKEMLESIR ETAEEPLSIQ SLRFLQLELS
EMEAFVNQHK SNSIKRQTVI TTMTTLKKNL ADEDAVSCLV LGTENKELLV LDPEAFTILA
KMSLPSVPVF LEVSGQFDVE FRLAAACRNG NIYILRRDSK HPKYCIELSA QPVGLIRVHK
VLVVGSTQDS LHGFTHKGKK LWTVQMPAAI LTMNLLEQHS RGLQAVMAGL ANGEVRIYRD
KALLNVIHTP DAVTSLCFGR YGREDNTLIM TTRGGGLIIK ILKRTAVFVE GGSEVGPPPA
QAMKLNVPRK TRLYVDQTLR EREAGTAMHR AFQTDLYLLR LRAARAYLQA LESSLSPLST
TAREPLKLHA VVQGLGPTFK LTLHLQNTST TRPVLGLLVC FLYNEALYSL PRAFFKVPLL
VPGLNYPLET FVESLSNKGI SDIIKVLVLR EGQSAPLLSA HVNMPGSEGL AAA
//

MIM 209900
*RECORD*
*FIELD* NO
209900
*FIELD* TI
#209900 BARDET-BIEDL SYNDROME; BBS
BARDET-BIEDL SYNDROME 1, INCLUDED; BBS1, INCLUDED;;
read moreBARDET-BIEDL SYNDROME 2, INCLUDED; BBS2, INCLUDED;;
BARDET-BIEDL SYNDROME 3, INCLUDED; BBS3, INCLUDED;;
BARDET-BIEDL SYNDROME 4, INCLUDED; BBS4, INCLUDED;;
BARDET-BIEDL SYNDROME 5, INCLUDED; BBS5, INCLUDED;;
BARDET-BIEDL SYNDROME 6, INCLUDED; BBS6, INCLUDED;;
BARDET-BIEDL SYNDROME 7, INCLUDED; BBS7, INCLUDED;;
BARDET-BIEDL SYNDROME 8, INCLUDED; BBS8, INCLUDED;;
BARDET-BIEDL SYNDROME 9, INCLUDED; BBS9, INCLUDED;;
BARDET-BIEDL SYNDROME 10, INCLUDED; BBS10, INCLUDED;;
BARDET-BIEDL SYNDROME 11, INCLUDED; BBS11, INCLUDED;;
BARDET-BIEDL SYNDROME 12, INCLUDED; BBS12, INCLUDED;;
BARDET-BIEDL SYNDROME 13, INCLUDED; BBS13, INCLUDED;;
BARDET-BIEDL SYNDROME 14, INCLUDED; BBS14, INCLUDED;;
BARDET-BIEDL SYNDROME 15, INCLUDED; BBS15, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because Bardet-Biedl syndrome
is a genetically heterogeneous disorder. BBS1 is associated with
mutations in a gene on chromosome 11q13 (209901); BBS2, with mutations
in a gene on 16q21 (606151); BBS3, with mutations in the ARL6 gene on
3p12-q13 (608845). BBS4 is caused by mutation in a gene on 15q22.3
(600374); BBS5, by mutation in a gene on 2q31 (603650); BBS6, by the
MKKS gene on 20p12 (604896), mutations in which also cause
McKusick-Kaufman syndrome (236700); BBS7, by mutation in a gene on 4q27
(607590). BBS8 is caused by mutation in the TTC8 gene on chromosome
14q32.11 (608132); BBS9, by mutation in a gene on 7p14 (607968); BBS10,
by mutation in a gene on 12q (610148); BBS11, by mutation in the TRIM32
gene on 9q33.1 (602290); BBS12, by mutation in a gene on 4q27 (610683).
BBS13 is caused by mutation in the MKS1 gene (609883) on chromosome
17q23, mutations in which also cause Meckel syndrome-1 (249000). BBS14
is caused by mutation in the CEP290 gene (610142) on 12q21.3, mutations
in which also cause Meckel syndrome-4 (611134) and several other
disorders. BBS15 is caused by mutation in the C2ORF86 gene (613580),
which encodes a homolog of the Drosophila planar cell polarity gene
'fritz.'

The CCDC28B gene (610162) modifies the expression of BBS phenotypes in
patients who have mutations in other genes. Mutations in MKS1, MKS3
(TMEM67; 609884), and C2ORF86 also modify the expression of BBS
phenotypes in patients who have mutations in other genes.

Although BBS had been originally thought to be a recessive disorder,
Katsanis et al. (2001) demonstrated that clinical manifestation of some
forms of Bardet-Biedl syndrome requires recessive mutations in 1 of the
6 loci plus an additional mutation in a second locus. While Katsanis et
al. (2001) called this 'triallelic inheritance,' Burghes et al. (2001)
suggested the term 'recessive inheritance with a modifier of
penetrance.' Mykytyn et al. (2002) found no evidence of involvement of
the common BBS1 mutation in triallelic inheritance. However, Fan et al.
(2004) found heterozygosity in a mutation of the BBS3 gene (608845.0002)
as an apparent modifier of the expression of homozygosity of the
met390-to-arg mutation in the BBS1 gene (209901.0001).

Allelic disorders include nonsyndromic forms of retinitis pigmentosa,
RP51 (613464), caused by TTC8 mutation, and RP55 (613575), caused by
ARL6 mutation.

CLINICAL FEATURES

Renal abnormalities appear to have a high frequency in the Bardet-Biedl
syndrome (Alton and McDonald, 1973). Klein (1978) observed 57 cases of
Bardet-Biedl syndrome in Switzerland. Fifteen affected individuals
occurred in one inbred pedigree and 7 in a second. Pagon et al. (1982)
reported a 12-year-old boy with the Bardet-Biedl syndrome (retinal
dystrophy, polydactyly, mental retardation, and mild obesity) who died
of renal failure and was found to have hepatic fibrosis. They reviewed
both earlier reported cases and other autosomal recessive entities that
combine retinal dystrophy, hepatic fibrosis and nephronophthisis.
Harnett et al. (1988) evaluated 20 of 30 patients with Bardet-Biedl
syndrome identified from ophthalmologic records in Newfoundland. All had
some abnormality in renal structure, function, or both. Most had minor
functional abnormalities and a characteristic radiologic appearance, but
to date (the mean age was 31 years) only 3 of the 20 had end-stage renal
disease, with 2 requiring maintenance hemodialysis. Half the subjects
had hypertension. Calyceal clubbing or blunting was evident in 18 of 19
patients studied by intravenous pyelography; 13 had calyceal cysts or
diverticula. Of the 19 patients, 17 had lobulated renal outlines of the
fetal type.

Green et al. (1989) examined 32 patients with Bardet-Biedl syndrome for
some or all of the cardinal manifestations of the disorder. Of 28
patients examined, all had severe retinal dystrophy, but only 2 had
typical retinitis pigmentosa. Polydactyly was present in 18 of 31
patients; syndactyly, brachydactyly, or both were present in all
patients. Obesity was present in all but 1 of 25 patients. Only 13 of 32
patients were considered mentally retarded. Scores on verbal subsets of
intelligence were usually lower than scores on performance tasks. Of 8
men, 7 had small testes and genitalia, which was not due to
hypogonadotropism. All 12 women studied had menstrual irregularities and
3 had low serum estrogen levels (1 of these had hypogonadotropism and 2
had primary gonadal failure). Diabetes mellitus was present in 9 of 20
patients. Renal structural or functional abnormalities were present in
all 21 patients studied, and 3 patients had end-stage renal failure.

Gershoni-Baruch et al. (1992) emphasized the occurrence of cystic kidney
dysplasia in Bardet-Biedl syndrome. They commented on the fact that the
combination of cystic kidney dysplasia and polydactyly occurs also in
Meckel syndrome (249000) and in the short rib-polydactyly syndromes (see
613091), and that usually these syndromes are easy to differentiate.
They observed 3 sibs with cystic kidney dysplasia and polydactyly who
were thought to have Meckel syndrome until extinguished responses on
electroretinography were detected in one of them, aged 3.5 years. In
19-year-old female twins and their 22-year-old sister, Chang et al.
(1981) described hypogonadotropic hypogonadism with primary amenorrhea
and lack of secondary sexual development, associated with retinitis
pigmentosa.

Stoler et al. (1995) described 2 unrelated girls with Bardet-Biedl
syndrome who also had vaginal atresia. A similar association was
suggested in reports of 11 BBS females who had structural genital
abnormalities (some of which were missed in childhood), including
persistent urogenital sinus; ectopic urethra; hypoplasia of the uterus,
ovaries, and fallopian tubes; uterus duplex; and septate vagina.
Mehrotra et al. (1997) observed 2 sisters with the Bardet-Biedl
syndrome, 1 of whom had congenital hydrometrocolpos. This infant also
had tetramelic postaxial polydactyly, making the diagnosis of
Kaufman-McKusick syndrome (236700) a possibility in the neonatal period.
However, as a teenager she was evaluated for poor vision and found to
have mental deficiency, obesity, poor visual acuity, end gaze nystagmus,
tapetoretinal degeneration, and extinguished electroretinogram. Her
older sister had similar eye complaints; she likewise was born with
tetramelic postaxial polydactyly and was also mentally retarded.

David et al. (1999) reported 9 patients who, because of the presence of
vaginal atresia and postaxial polydactyly, were diagnosed in infancy
with McKusick-Kaufman syndrome; these patients later developed obesity
and retinal dystrophy and were diagnosed with Bardet-Biedl syndrome.
David et al. (1999) suggested that the phenotypic overlap between
McKusick-Kaufman syndrome and Bardet-Biedl syndrome is a diagnostic
pitfall, and that all children in whom a diagnosis of McKusick-Kaufman
syndrome is made in infancy should be reevaluated for retinitis
pigmentosa and other signs of Bardet-Biedl in later childhood.

In Bedouin families in the Negev region of Israel, presumably the same
kindreds as those studied by Kwitek-Black et al. (1993), Elbedour et al.
(1994) performed echocardiographic evaluations of cardiac involvement in
BBS. They stated that they found cardiac involvement in 50% of cases,
justifying inclusion of echocardiographic examination in the clinical
evaluation and follow-up of these patients. However, their Table 1 gives
echocardiographic abnormality in only 7 of 22 cases and these included 1
case of bicuspid aortic valve, 1 case of mild thickening of the
interventricular septum, 1 case of 'moderate tricuspid regurgitation,'
and 1 case of mild pulmonic valve stenosis. The occurrence of renal
abnormality in 11 of the 22 patients on kidney ultrasonography was
somewhat more impressive than the cardiac involvement.

Islek et al. (1996) described a boy with postaxial polydactyly and
Hirschsprung disease (142623) found at the age of 3 months. Follow-up
examination at the age of 7 years showed obesity, mental retardation,
retinitis pigmentosa, microphallus, and cryptorchidism. The diagnosis of
Bardet-Biedl syndrome was established. According to Islek et al. (1996),
2 other cases of association of Bardet-Biedl syndrome and Hirschsprung
disease have been reported.

Beales et al. (1999) reported a study of 109 BBS patients and their
families. Average age at diagnosis was 9 years. Postaxial polydactyly
was present in 69% of patients at birth, but obesity did not begin to
develop until approximately 2 to 3 years of age, and retinal
degeneration did not become apparent until a mean age of 8.5 years. As a
result of their study, Beales et al. (1999) proposed a set of diagnostic
criteria based on primary and secondary features. They suggested the use
of the term polydactyly-obesity-kidney-eye syndrome in recognition of
what they described as the phenotypic overlap between BBS and
Laurence-Moon syndrome.

In 2 patients with Bardet-Biedl syndrome, Lorda-Sanchez et al. (2000)
identified 2 uncommon manifestations: situs inversus in one and
Hirschsprung disease in the other. They were unable to determine which
of the 5 forms of BBS known at that time was present in these cases.

Cox et al. (2003) examined the electrophysiologic responses of carriers
of BBS. All carriers had decreased corneal positive potential and 60%
had a decreased b-wave sensitivity. The authors postulated that the site
of the primary defect in the BBS rod pathway appeared to be proximal to
the rod outer segments, most likely before the rod-bipolar cell synapse.

Kulaga et al. (2004) showed that individuals with BBS have partial or
complete anosmia (107200). To test whether this phenotype is caused by
ciliary defects of olfactory sensory neurons, they examined mice with
deletions of Bbs1 or Bbs4 (600374) genes. Loss of function of either BBS
protein affected the olfactory, but not the respiratory, epithelium,
causing severe reduction of the ciliated border, disorganization of the
dendritic microtubule network and trapping of olfactory ciliary proteins
in dendrites and cell bodies.

Iannaccone et al. (2005) described decreased olfaction in 2 individuals
from a 5-generation Italian family with BBS4 previously reported by
Mykytyn et al. (2001) (see 600374.0002). They concluded that the BBS4
gene plays a role in olfaction, supporting the hypothesis that ciliary
dysfunction is an important aspect of BBS pathogenesis. They suggested
that the spectrum of clinical manifestations associated with BBS be
broadened to include decreased olfaction.

Deffert et al. (2007) reported 2 brothers, born of consanguineous
Algerian parents, with clinical features of BBS although no causative
mutation was identified in the BBS1 through BBS10 genes. In addition to
diagnostic criteria, both boys had insertional polydactyly and situs
inversus. One brother developed cone-rod dystrophy in childhood and the
other developed progressive vision loss at age 15 years resulting in
blindness by 18 years. See 606568.0001 and Marion et al. (2012).

By detailed neurologic examination of 9 BBS patients, Tan et al. (2007)
observed a noticeable decrease in peripheral sensation affecting all
modalities in most patients. Tan et al. (2007) concluded that this may
be an underrecognized component of the disorder.

- Relationship to Laurence-Moon Syndrome

There has been longstanding uncertainty as to the relationship between
the Laurence-Moon syndrome (245800) and the Bardet-Biedl syndrome.
Solis-Cohen and Weiss (1925) lumped them together as the Laurence-Biedl
syndrome. Ammann (1970) concluded that the patients of Laurence and Moon
had a distinct disorder with paraplegia and without polydactyly and
obesity. As suggested by the study of Ammann (1970), residual
heterogeneity may exist even after the Laurence-Moon syndrome is
separated; for example, Biemond syndrome II (iris coloboma,
hypogenitalism, obesity, polydactyly, and mental retardation; 213350)
and Alstrom syndrome (retinitis pigmentosa, obesity, diabetes mellitus,
and perceptive deafness; 203800) were considered distinct entities.
Schachat and Maumenee (1982) reviewed the nosography of these and
related syndromes.

In a 22-year prospective cohort study of 46 patients from 26
Newfoundland families with BBS, Moore et al. (2005) found no apparent
correlation of clinical or dysmorphic features with genotype. They
reported that of 2 patients clinically diagnosed as having Laurence-Moon
syndrome, one was from a consanguineous pedigree with linkage to the
BBS5 gene, and the other was a compound heterozygote for mutations in
the MKKS gene (604896.0007 and 604896.0008). Moore et al. (2005)
concluded that the features in this population did not support the
notion that BBS and LMS are distinct. The patient with mutations in the
MKKS gene (NF-B5) had previously been reported by Katsanis et al. (2000)
as having BBS6, thus illustrating the difficulty in distinguishing these
2 disorders.

- Bardet-Biedl Syndrome 1

Beales et al. (1997) observed only subtle phenotypic differences among
Bardet-Biedl families mapping to the BBS1, BBS2, or BBS4 loci, the most
striking of which was the finding of taller affected offspring compared
with their parents in the BBS1 category. Affected subjects in the BBS2
and BBS4 groups were significantly shorter than their parents. In more
than one-fourth of the pedigrees, linkage to no known locus could be
established, suggesting the existence of a fifth BBS locus.

- Bardet-Biedl Syndrome 3

Sheffield et al. (1994) reported that the clinical features of Bedouin
families with BBS2 and BBS3 were very similar. For example, all affected
individuals in both kindreds showed postaxial polydactyly. The authors
hypothesized that the identical phenotype resulting from different
mutations at 2 separate loci might have its explanation in involvement
of a ligand-receptor complex, protein subunits, or proteins involved in
a common biochemical pathway.

In the Newfoundland kindred of Northern European descent with BBS3
described by Young et al. (1998), the BBS3 phenotype, which includes
polydactyly of all 4 extremities, mental retardation, and progression to
morbid obesity, was not observed. Patients had polydactyly limited to
the lower limbs, average IQ, and obesity reversible by caloric
restriction and/or exercise.

Ghadami et al. (2000) reported an Iranian family with BBS3 in 7 members.
Linkage analysis showed that this was indeed BBS3. All patients had a
history of mild to severe obesity, which was reversible in some patients
by caloric restriction and exercise. All patients had pigmentary
retinopathy, beginning as night blindness in early childhood and
progressing toward severe impairment of vision by the end of the second
decade. Polydactyly varied in limb distribution, ranging from 4-limb
involvement to random involvement or even to lack of polydactyly. Six of
the 7 patients were not mentally retarded. Although kidney anomaly or an
adrenal mass was present in 2 patients, the fact that 1 patient had 7
children ruled out reproductive dysfunction. Comparison of clinical
manifestations with those of previously reported BBS3 patients did not
support any type-specific phenotypes.

- Bardet-Biedl Syndrome 5

Young et al. (1999) reported that in 5 affected members of a BBS5
kindred, related as sibs or first cousins in 3 sibships and of ages
varying from 21 to 31 years, none had polydactyly, but all had
brachydactyly and/or syndactyly. All had severe visual impairment with
retinal macular changes, and in the 2 males examined, the penis was
small.

- Bardet-Biedl Syndrome 10

Putoux et al. (2010) identified homozygous or compound heterozygous
mutations in the C12ORF58 gene (see, e.g., 610148.0001; 610148.0006) in
5 of 21 patients with antenatal onset of severe renal cystic anomalies
and polydactyly, without the biliary or hepatic abnormalities
characteristic of Meckel syndrome (MKS; 249000). Four of the patients
were fetuses between ages 21 and 26 weeks' gestation, and the fifth was
a 20-year-old woman with BBS10 who was found to have hyperechogenic
kidneys and polydactyly on antenatal ultrasound. The most common
mutation was a 1-bp duplication (271dupT; 610148.0001), found on 6 of 10
mutant C12ORF58 alleles. The 20-year-old woman also carried a
heterozygous truncating mutation in the BBS6 gene. Putoux et al. (2010)
noted that the diagnosis of severe lethal BBS is suggested in utero by
the findings of severe cystic kidneys and polydactyly without biliary
dysgenesis or brain anomalies, and concluded that mutations in the
C12ORF58 gene may account for a high percentage of such cases.

- Bardet-Biedl Syndrome 12

Dulfer et al. (2010) reported 2 female sibs with BBS resulting from
compound heterozygous truncating mutations in the BBS12 gene. Each also
carried a third heterozygous mutation in the BBS10 gene. The first
patient had postaxial polydactyly type A and severe hydrometrocolpos,
resulting in prolonged delivery with hypoxia and death at delivery.
Examination showed atresia of the distal vagina, a dilated cervix and
uterus, and cystic renal dysplasia. The second pregnancy was terminated
at 15 weeks' gestation after chorionic villus sampling identified the
same 3 mutations in the second fetus, which had no external features of
BBS and no abnormalities of the internal genitalia, although cystic
renal dysplasia was present. Dulfer et al. (2010) noted the phenotypic
variability between these sibs, and suggested that hydrometrocolpos
should be considered a feature in females with BBS. The authors also
questioned whether the BBS10 mutation had any influence on the
phenotype, since the BBS12 mutations were sufficient to cause the
disorder.

INHERITANCE

Katsanis et al. (2001) screened 163 BBS families for mutations in both
BBS2 and BBS6 and reported the presence of 3 mutant alleles in affected
individuals in 4 pedigrees. In addition, Katsanis et al. (2001) detected
unaffected individuals in 2 pedigrees who carried 2 BBS2 mutations but
not a BBS6 mutation. One of these was found to be homozygous by descent
for a BBS1 allele, and the other was found to be homozygous by descent
for a BBS4 allele.

The identification of the gene most commonly mutated in individuals with
BBS (BBS1; 209901) allowed Mykytyn et al. (2002) to examine the
hypothesis that 3 mutated alleles are required for penetrance of the BBS
phenotype (triallelic inheritance), as had been suggested by Katsanis et
al. (2001). They did not find the common M390R mutation (209901.0001) in
any of 12 unrelated individuals who had previously been shown to have 2
mutations in BBS2, BBS4, or BBS6 (MKKS). Moreover, complete sequencing
of BBS1 in these individuals revealed no coding sequence variations. In
addition, they sequenced BBS2, BBS4, and MKKS in 10 unrelated North
American individuals who were homozygous with respect to the BBS1 M390R
mutation. All sequence alterations identified in affected individuals
were also found in controls. Although it is possible that these
individuals could harbor an additional mutated allele in an unidentified
gene underlying BBS, the fact that the remaining genes account for a
very small proportion of Bardet-Biedl syndrome makes this unlikely.
Finally, in 6 multiplex families in which affected individuals harbored
BBS1 mutations, Mykytyn et al. (2002) did not detect any unaffected
individuals with 2 BBS1 mutations. Thus, in the families studied by
them, the disorder segregated as an autosomal recessive disease, with no
evidence that BBS1 acts in triallelic inheritance.

Mykytyn et al. (2003) demonstrated that the common BBS1 M390R mutation
accounts for approximately 80% of all BBS1 mutations and is found on a
similar genetic background across populations.

Stoetzel et al. (2006) identified homozygous mutations in the TTC8 gene
(608132.0003 and 608132.0004) in 2 of 128 BBS families. One additional
family had a heterozygous mutation. Stoetzel et al. (2006) concluded
that mutations in the TTC8 gene account for only about 2% of BBS
families.

Stoetzel et al. (2006) found that the BBS10 gene (610148) was mutated in
about 20% of an unselected cohort of families of various ethnic origins.
Notably, they found a similar frequency of mutations among families of
Middle Eastern ancestry as among those of European ancestry. Twelve of
65 (18%) families with BBS10 mutations also had mutations or recognized
variants at another BBS locus, indicative of a potential epistatic
interaction.

In affected members of 3 sibships within a large consanguineous Lebanese
kindred with BBS reported by Stoetzel et al. (2006), Laurier et al.
(2006) found homozygosity for a mutation in the BBS10 gene
(610148.0004). The only affected individual from a fourth sibship within
this kindred was compound heterozygosity for 2 mutations in the BBS10
gene (610148.0004 and 610148.0005). In addition, 2 affected individuals
from a fifth sibship within this kindred were homozygous for a mutation
in the BBS2 gene (606151.0017). There was no evidence for triallelism in
this kindred, although 3 different mutations in 2 different genes (BBS2
and BBS10) were found. Laurier et al. (2006) commented on the unusual
finding of homozygosity and compound heterozygosity for mutations in 2
different genes within a single large consanguineous kindred.

Abu-Safieh et al. (2012) presented evidence that most cases of BBS are
inherited in a classic autosomal recessive pattern, and that the
triallelic model is very rare, if it exists at all. The authors
conducted a comprehensive sequence analysis of all 14 BBS genes as well
as the modifier gene CCDC28B (610162) in a cohort of 29 Arab BBS
families. Two pathogenic mutations in trans were identified in affected
members of each family, and in no instance was a third allele identified
that convincingly acted as a modifier of penetrance supporting the
triallelic model of BBS. The massive sequencing effort uncovered a
number of novel sequence variants in BBS genes other than the 2
pathogenic mutations per family, but the majority of these variants were
noncoding and none of the possible splicing variants were predicted to
be pathogenic.

HETEROGENEITY

Type 1 Bardet-Biedl syndrome (BBS1) is caused by mutation in a gene that
maps to chromosome 11q13 (209901). Bardet-Biedl syndrome type 2 (BBS2)
is caused by mutation in a gene that maps to chromosome 16q21 (606151).
Bardet-Biedl syndrome type 3 (BBS3) is caused by mutation in the
ADP-ribosylation factor (ARF)-like-6 gene (ARL6; 608845) on chromosome
3p13-p12. Bardet-Biedl syndrome type 4 (BBS4) is caused by mutation in a
gene that maps to chromosome 15q22.3-q23 (600374). Bardet-Biedl syndrome
type 5 (BBS5) is caused by mutation in a gene that maps to chromosome
2q31 (603650). Bardet-Biedl syndrome type 6 (BBS6) is caused by mutation
in the same gene, MKKS (604896), located on 20p12, that is mutant in
McKusick-Kaufman syndrome (236700). Bardet-Biedl syndrome type 7 (BBS7)
is caused by mutation in a gene that maps to chromosome 4q27 (607590).
Mutation in a tetratricopeptide repeat protein, TTC8 (608132), causes
Bardet-Biedl syndrome type 8 (BBS8). Mutation in the parathyroid
hormone-responsive gene B1 (PTHB1; 607968) causes Bardet-Biedl syndrome
type 9 (BBS9). Mutation in the C12ORF58 gene (610148) causes
Bardet-Biedl syndrome type 10 (BBS10). Mutation in the tripartite
motif-containing protein-32 gene (TRIM32; 602290) causes Bardet-Biedl
syndrome type 11 (BBS11). Mutation in the C4ORF24 gene (610683) causes
Bardet-Biedl syndrome type 12. Bardet-Biedl syndrome type 13 (BBS13) is
caused by mutation in the MKS1 gene (609883). Bardet-Biedl syndrome type
14 (BBS14) is caused by mutation in the CEP290 gene (610142).
Bardet-Biedl syndrome type 15 (BBS15) is caused by mutation in the
C2ORF86 gene (613580).

MOLECULAR GENETICS

In a population-based study including 93 BBS patients from 74 families
of various ethnicities, Billingsley et al. (2010) determined that the
chaperonin-like BBS6, BBS10, and BBD12 genes are a major contributor to
the disorder. Biallelic mutations in these 3 genes were found in 36.5%
of the families: 4 patients had mutations in BBS6, 19 had mutations in
BBS10, and 10 had mutations in BBS12. Overall, 26 (68%) of 38 mutations
were novel. Six patients had mutations present in more than 1
chaperonin-like BBS gene, and 1 patient with a very severe phenotype had
4 mutations in BBS10. The phenotypes observed were beyond the classic
BBS phenotype and overlapped with characteristics of MKKS (236700),
including congenital heart defect, vaginal atresia, hydrometrocolpos,
and cryptorchidism, and with Alstrom syndrome (203800), including
diabetes, hearing loss, liver abnormalities, endocrine anomalies, and
cardiomyopathy.

Muller et al. (2010) screened the BBS1 through BBS12 genes and
identified pathogenic mutations in 134 (77%) of 174 BBS families: 117
families had 2 pathogenic mutations in a single gene, and 17 families
had a single heterozygous mutation, 8 of which were the BBS1 recurrent
mutation M390R (209901.0001). BBS1 and BBS10 were the most frequently
mutated genes, each found in 32.6% of families, followed by BBS12, found
in 10.4% of families. No mutations were found in BBS11, which has only
been identified in 1 consanguineous family. There was a high level of
private mutations, and Muller et al. (2010) discussed various strategies
for diagnostic mutation detection, including homozygosity mapping and
targeted arrays for the detection of previously reported mutations.

By homozygosity mapping followed by exon enrichment and next-generation
sequencing in 136 consanguineous families (over 90% Iranian and less
than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms
of autosomal recessive intellectual disability, Najmabadi et al. (2011)
identified homozygosity for a 6-bp deletion in the BBS7 gene
(607590.0004) in affected members of a family (M324) segregating
Bardet-Biedl syndrome.

- Modifier Genes

The CCDC28B gene (610162) modifies the expression of BBS phenotypes in
patients who have mutations in other genes. Mutations in MKS1, MKS3
(TMEM67; 609884), and C2ORF86 also modify the expression of BBS
phenotypes in patients who have mutations in other genes.

Putoux et al. (2011) identified 8 different heterozygous missense
mutations in the KIF7 gene (611254) in 8 patients with ciliopathies,
including Bardet-Biedl syndrome, Meckel syndrome (MKS; 249000), Joubert
syndrome (JBTS; 213300), Pallister-Hall syndrome (PHS; 146510), and OFD6
(277170). Four of these patients had additional pathogenic mutations in
other BBS genes. Rescue studies of somites in morphant zebrafish embryos
demonstrated that the heterozygous KIF7 missense mutations were
hypomorphs, and Putoux et al. (2011) concluded that these alleles may
contribute to or exacerbate the phenotype of other ciliopathies,
particularly BBS.

DIAGNOSIS

Janssen et al. (2011) used a DNA pooling and massively parallel
resequencing strategy to screen 132 individuals with BBS from 105
families. This method allowed identification of both disease-causing
mutations in 29 (28%) of 105 families. Thirty-five different
disease-causing mutations were identified, 18 of which were novel.

GENOTYPE/PHENOTYPE CORRELATIONS

Carmi et al. (1995) compared the clinical manifestations of BBS in 3
unrelated, extended Arab-Bedouin kindreds in which linkage had been
demonstrated to chromosomes 3 (BBS3), 15 (BBS4), and 16 (BBS2). Observed
differences included the limb distribution of the postaxial polydactyly
and the extent and age-association of obesity. It appeared that the
chromosome 3 locus is associated with polydactyly of all 4 limbs, while
polydactyly of the chromosome 15 type is mostly confined to the hands.
The chromosome 15 type is associated with early-onset morbid obesity,
while the chromosome 16 type appears to present the 'leanest' end of
BBS.

Khanna et al. (2009) presented evidence that a common allele in the
RPGRIP1L gene (A229T; 610937.0013) may be a modifier of retinal
degeneration in patients with ciliopathies due to other mutations,
including BBS.

- BBS Gene Heterozygosity

On the basis of a study of 75 relatives in 5 generations of the extended
family of 2 adult Bardet-Biedl sibs, Croft and Swift (1990) suggested
that heterozygotes have an increased frequency of obesity, hypertension,
diabetes mellitus, and renal disease. They pointed out that homozygotes
have hepatic disease.

Croft et al. (1995) studied obesity and hypertension among nonhomozygous
relatives of BBS patients, hypothesizing that BBS heterozygotes might be
predisposed to these conditions. Among 34 parents of BBS homozygotes
(obligate heterozygotes), a proportion of severely overweight fathers
(26.7%) were significantly higher than that in comparably aged U.S.
white males (8.9%). They concluded that the BBS gene may predispose male
heterozygotes to obesity. If heterozygotes represent 1% of the general
population, they estimated that approximately 2.9% of all severely
overweight white males carry a single BBS gene. The BBS parents of both
sexes were also significantly taller than U.S. white men and women of
comparable age.

Beales et al. (1999) found renal cell adenocarcinomas in 3 parents of
individuals with BBS, and congenital renal malformations in a number of
others. They suggested that these findings may be a consequence of
heterozygosity for disease-causing mutations in BBS genes.

MAPPING

In a study of 19 BBS families of mixed but predominantly European ethnic
origin, Bruford et al. (1997) obtained results showing that an estimated
36 to 56% of the families were linked to 11q13. A further 32 to 35% of
the families were linked to 15q22.3-q23. Three consanguineous families
showed homozygosity for 3 adjacent chromosome 15 markers, consistent
with identity by descent for this region. In one of these families
haplotype analysis reported a localization for BBS4 between D15S131 and
D15S114, a distance of about 2 cM. Weak evidence of linkage to 16q21 was
observed in 24 to 27% of families. A fourth group of families, estimated
at 8%, were unlinked to all 3 of the above loci. Bruford et al. (1997)
found no evidence of linkage to markers on chromosome 3, corresponding
to the BBS3 locus, or on chromosome 2 or 17, arguing against the
involvement of a BBS locus in a patient with Bardet-Biedl syndrome and a
t(2;17) translocation reported by Dallapiccola (1971).

The prevalence of BBS in Newfoundland is approximately 10-fold greater
than in Switzerland (1 in 160,000) and similar to the prevalence among
the Bedouin of Kuwait (1 in 13,500). Woods et al. (1999) performed a
population-based genetic survey of 17 BBS families in the island portion
of the province of Newfoundland. The families contained a total of 36
well-documented affected individuals; 12 families had 2 or more affected
persons. Linkage at each of the 4 then-known loci was tested with
2-point linkage and haplotype analysis. Three of the kindreds showed
linkage to 11q (BBS1), 1 to 16q (BBS2), and 1 to 3p (BBS3). The BBS3
family was the first to be identified in a population of northern
European descent. Six families remained undetermined because of poor
pedigree structure or inconclusive haplotype analyses. Six families were
excluded from all 4 then-known BBS loci, including BBS4.

In a study of 7 Saudi Arabian BBS families, Safieh et al. (2010)
demonstrated that homozygosity mapping was an efficient approach to
identifying causative mutations, because it allowed them to sequence
only 1 gene per family and find 7 novel mutations, respectively: 3 in
the BBS1 gene, 3 in the BBS3 gene, and 1 in the BBS4 gene. Six of the
families displayed the typical constellation of findings for BBS, which
varied in frequency between families but were highly consistent within
families, suggesting that modifiers appear to play only a minor role in
the expressivity of BBS. In the remaining family, previously reported by
Aldahmesh et al. (2009), a homozygous BBS3 mutation (608845.0006)
segregated with nonsyndromic autosomal recessive RP (RP55; 613575).
Compared with earlier reports, Safieh et al. (2010) stated that their
data were consistent with a trend towards milder severity in patients
with BBS3 mutations, since all cases of documented normal male fertility
or lack of cognitive impairment belonged to this category. In addition,
atopy appeared to be a common clinical feature that was not restricted
to a specific genotype, and none of their patients reported a history of
hyposmia, suggesting that this is an uncommon finding.

Harville et al. (2010) independently used homozygosity mapping in a
worldwide cohort of 45 BBS families to identify 17 causative homozygous
mutations in 20 families, in the BBS1, BBS2, BBS4, BBS5, BBS7, BBS8,
BBS10, and BBS12 genes. Three mutations occurred in 2 unrelated families
each, and 11 of the 17 mutations were novel; none of the mutations were
found in more than 90 ethnically matched controls. Harville et al.
(2010) concluded that whole-genome homozygosity mapping followed by
direct sequencing is an effective alternative means of identifying
causative mutations in disorders of striking genetic heterogeneity such
as BBS.

- Linkage to 11q13 (BBS1)

Leppert et al. (1994) performed linkage analysis in 31 multiplex BBS
families and reported linkage with 2 markers on 11q, PYGM (608455) and
an anonymous marker, D11S913. The homozygosity testing demonstrated
genetic heterogeneity within the set of families. The confidence
interval for BBS1, based on a 1 lod difference, extended approximately 1
cM proximal to PYGM and 2 cM distal to PYGM. PYGM is located in band
11q13. Leppert et al. (1994) stated that they had seen families unlinked
to either chromosome 16 (BBS2) or chromosome 11.

Beales et al. (1997) studied 18 families with 2 or more members affected
with Bardet-Biedl syndrome, noting the presence of both major and minor
manifestations. They performed linkage studies in the hope of finding
phenotypic differences between the 4 linkage categories identified to
that time. Eight of the families (44%) were found to be linked to 11q13
(BBS1), and 3 (17%) were linked to 16q21 (BBS2). Only 1 family was
linked to 15q22 (BBS4; 600374), and none were linked to 3p12 (BBS3;
608845). They concluded that BBS1 is the major locus among white
Bardet-Biedl patients and that BBS3 is extremely rare. Only subtle
phenotypic differences were observed, the most striking of which was the
finding of taller affected offspring compared with their parents in the
BBS1 category. Affected subjects in the BBS2 and BBS4 groups were
significantly shorter than their parents. In more than one-fourth of the
pedigrees, linkage to no known locus could be established, suggesting
the existence of a fifth BBS locus.

Katsanis et al. (1999) collected a large number of BBS pedigrees of
primarily North American and European origin and performed genetic
analysis using microsatellites from all known BBS genomic regions.
Heterogeneity analysis established a 40.5% contribution of the 11q13
locus to BBS, and haplotype construction on 11q-linked pedigrees
revealed several informative recombinants, defining the BBS1 critical
interval between D11S4205 and D11S913, a genetic distance of 2.9 cM,
equivalent to approximately 2.6 Mb. Loss of identity by descent in 2
consanguineous pedigrees was also observed in the region, potentially
refining the region to 1.8 Mb between D11S1883 and D11S4944.

Young et al. (1999) used linkage disequilibrium (LD) mapping in an
isolated founder population in Newfoundland to reduce significantly the
BBS1 critical region. Extensive haplotype analysis in several unrelated
BBS families of English descent revealed that the affected members were
homozygous for overlapping portions of a rare, disease-associated
ancestral haplotype. The LD data suggested that the BBS1 gene lies in a
1-Mb, sequence-ready region on 11q13.

- Linkage to 16q21 (BBS2)

Kwitek-Black et al. (1993) performed linkage studies in a large inbred
Bedouin family from the Negev region of Israel. All 9 affected persons
had polydactyly and pigmented retinopathy. Linkage and the candidate
gene approach were used to exclude all known autosomal pigmented
retinopathy loci. Thereafter, a genomewide search for linkage was
conducted using short tandem repeat polymorphisms (STRPs). By this
approach, they identified linkage of the BBS locus to markers that
mapped to 16q21. Maximum likelihood calculations for 2-point linkage
between D16S408 and the disease phenotype resulted in Z = 4.2 at theta =
0.0. A multilocus lod score of 5.3 was observed. By demonstrating
homozygosity in all affected individuals for the same allele of marker
D16S408, further support for linkage was found, and the utility of
homozygosity mapping using inbred families was demonstrated. In a second
family with BBS from a different Bedouin tribe and unrelated to the
first family, linkage to the same chromosome 16 markers was excluded
over a stretch of at least 20 cM centered on marker D16S408. The symbol
BBS2 was used for the locus on chromosome 16 and BBS1 for the
non-chromosome 16 locus (McAlpine, 1994).

Nishimura et al. (2001) used physical mapping and sequence analysis to
identify the BBS2 gene at 16q21. An open reading frame of 2,163 bp was
distributed over 17 exons. The gene is evolutionarily conserved and
displays a wide pattern of tissue expression, including brain, kidney,
adrenal gland, and thyroid gland. Mutations in the gene were identified
in 3 of 18 unrelated BBS families.

- Linkage to 3p13 (BBS3)

Using conventional linkage analysis of an inbred Bedouin kindred,
Sheffield et al. (1994) demonstrated linkage of the disease locus to
chromosome 3 in a 11-cM region between D3S1254 and D3S1302 (loci
identified by short tandem repeat polymorphisms; STRPs). They commented
that the locus was not near any of the known human retinopathy loci and
was not in a region of syntenic homology with any known mouse obesity
locus. They thus demonstrated that there are 2 genetic forms of BBS in
the Bedouin population of the Middle East, one determined by a
chromosome 16 gene (BBS2; 606151) and one determined by a chromosome 3
gene (BBS3).

Linkage of Bardet-Biedl syndrome to chromosome 3 in the kindred studied
by Sheffield et al. (1994) was supported by a lod score of 7.52 at theta
= 0.0, as well as by the observation of homozygosity in highly
informative markers across the candidate region in affected individuals.
From the location of the markers it was concluded that the BBS3 locus is
situated in 3p13-p12. This finding in a highly inbred kindred permitted
Sheffield et al. (1994) to test an efficient strategy for linkage
mapping. The approach consisted of pooling equal amounts of DNA from
each affected individual in the kindred. The affected DNA pool was then
used as a template for PCR with primers for genetic markers. Markers not
linked to the genetic disorder had multiple alleles in the pool sample,
whereas linked markers demonstrated a shift in allele frequency towards
a single allele. A marker completely linked to a recessive disease
showed a single allele when amplified from DNA pooled from affected
individuals from a single pedigree. This approach required that a single
common progenitor contributed the disease allele to all affected
individuals. Sheffield et al. (1994) suggested that the pooling strategy
should be well suited not only for studying recessive disorders in
genetically isolated populations but also for dominant disorders in
other instances where there is identity by descent. Quantitative trait
loci (QTLs) in genetically isolated populations could be studied by
comparing 2 pools consisting of individuals displaying the 2 extremes of
the phenotype.

Young et al. (1998) described a Newfoundland kindred of Northern
European descent with BBS and narrowed the chromosome 3p critical region
to 6 cM between D3S1595 and D3S1753.

- Linkage to 15q22.3 (BBS4)

Carmi et al. (1995) used a DNA pooling approach with DNA samples from a
highly inbred Bedouin kindred to identify a Bardet-Biedl syndrome locus
on chromosome 15. Homozygosity mapping using pooled DNA samples assumes
that all or most of the affected individuals share a common chromosomal
region inherited from a common ancestral founder. The pooled DNA was
used as a PCR template with primers for short tandem repeat
polymorphisms (STRPs). Pools consisting of DNA from unaffected sibs and
parents of affected individuals were used as controls. Markers not
linked to the disease locus are expected to show similar allele
frequencies in the affected and controlled pools as a result of
independent assortment. On the other hand, STRPs in linkage
disequilibrium with the disease phenotype show a shift in allele
frequencies toward a single homozygous allele in the affected DNA pool.
Following identification of linked loci by linkage disequilibrium
(homozygosity mapping), individual members of the pedigree were
genotyped using the STRP markers. All 8 STRPs resulted in a positive lod
score. Carmi et al. (1995) commented that the locus on chromosome 15 in
the q22.3-q23 region is not near any of the known human retinopathy loci
and is not in the region of syntenic homology with any of the known
mouse obesity loci. The phenotype of the patients in the chromosome 15
kindred was very similar to that described for the previously linked
loci. Identification of the genes involved in these 4 genetic forms of
BBS may aid in the understanding of common disorders such as obesity,
hypertension, and diabetes.

- Linkage to 2q31 (BBS5)

By a genomewide scan of pooled DNA samples using microsatellite markers
in a family with BBS, Young et al. (1999) demonstrated that the BBS5
locus maps to 2q31. The 2q31 region is close to the HOXD gene cluster
(142987), but refined mapping of the recombinant ancestral chromosome
excluded all genes within that cluster as candidates for BBS5.

- Linkage to 20p12 (BBS6)

Slavotinek et al. (2000) and Katsanis et al. (2000) independently
identified a form of Bardet-Biedl syndrome caused by mutations in the
MKKS gene (see, e.g., 604896.0009), a chaperonin-like gene in which
mutations associated with McKusick-Kaufman syndrome had been found.
Slavotinek et al. (2000) sought mutations in the MKKS gene because of
phenotypic similarities between McKusick-Kaufman syndrome and
Bardet-Biedl syndrome. McKusick-Kaufman syndrome includes
hydrometrocolpos, postaxial polydactyly, and congenital heart disease,
with autosomal recessive inheritance. Bardet-Biedl syndrome is likewise
an autosomal recessive disorder and is characterized by obesity, retinal
dystrophy, polydactyly, learning difficulties, hypogenitalism, and renal
malformations, with secondary features that include diabetes mellitus.
Five distinct forms of Bardet-Biedl syndrome, BBS1-5, had been
distinguished on the basis of linkage analysis. Katsanis et al. (2000)
performed a genome screen in BBS families from Newfoundland in which
BBS1 types 1 through 5 had been excluded and found linkage to a region
of chromosome 20 encompassing the MKKS gene.

Beales et al. (2001) collected a cohort of 163 BBS pedigrees from
diverse ethnic backgrounds and evaluated them for mutations in the MKKS
gene and for potential assignment of the disorder to any of the other
known BBS loci. Using a combination of mutation and haplotype analysis,
they described a spectrum of BBS6 alterations that are likely to be
pathogenic; proposed substantially reduced critical intervals for BBS2
(209900) on 16q21, BBS3 (608845) on 3p, and BBS5 (603650) on 2q; and
presented evidence for the existence of at least one more BBS locus,
bringing the total to 7. The data suggested that BBS6 is a minor
contributor to the syndrome and that some BBS6 alleles may act in
conjunction with mutations at other BBS loci to cause or modify the BBS
phenotype.

POPULATION GENETICS

Farag and Teebi (1988) concluded that the frequency of both the
Bardet-Biedl and the Laurence-Moon syndromes is increased in the Arab
population of Kuwait. Farag and Teebi (1989) pointed to a high frequency
of the Bardet-Biedl syndrome among the Bedouin; the estimated minimum
prevalence was 1 in 13,500.

PATHOGENESIS

Ansley et al. (2003) demonstrated that BBS is probably caused by a
defect of the basal body of ciliated cells. The TTC8 gene (608132),
mutations in which are responsible for BBS8, encodes a protein with a
prokaryotic domain, pilF, involved in pilus formation and twitching
mobility. In 1 family a homozygous null BBS8 mutation (608132.0002) led
to BBS with randomization of left-right body axis symmetry, a defect of
the nodal cilium. Ansley et al. (2003) showed that TTC8 localizes to
centrosomes and basal bodies and colocalizes with gamma-tubulin (see
191135), BBS4 (600374), and PCM1 (600299). Furthermore, Ansley et al.
(2003) found that all available C. elegans BBS homologs are expressed
exclusively in ciliated neurons and contain regulatory elements for RFX,
a transcription factor that modulates the expression of genes associated
with ciliogenesis and intraflagellar transport.

Bardet-Biedl syndrome is thought to result largely from ciliary
dysfunction, because loss-of-function mutations in the genes of C.
elegans homologous to BBS7 (607590) and BBS8 (608132) compromise cilia
structure and function, and RNA interference of Chlamydomonas BBS5
(603650) results in the loss of flagella. Notably, all known C. elegans
bbs genes are expressed exclusively in cells with cilia, owing to the
presence of a DAF-19 RFX transcription factor binding site (X box) in
their promoters. Fan et al. (2004) hypothesized that the C. elegans
ortholog of the human BBS3 gene would also contain this regulatory
element, which would allow them to identify candidates from among the
more than 90 genes that map to the BBS3 critical interval. One of 3
genes containing the X box in their promoters that determine exclusive
expression in cells with cilia was ARL6 (608845), making it a good
candidate for the BBS3 gene. Fan et al. (2004) indeed found mutations in
ARL6 segregating with BBS in 4 independent families.

Badano et al. (2006) identified MGC1203 (610162), also known as CCDC28B,
as contributing epistatic alleles to Bardet-Biedl syndrome.

Marion et al. (2009) found that human preadipocytes transiently formed a
primary cilium that carried Wnt (see WNT1; 164820) and hedgehog (see
SHH; 600725) receptors during preadipocyte differentiation.
Immunohistochemical showed that both BBS10 and BBS12 localized to the
basal body of this primary cilium. Knockdown of BBS10 and BBS12
expression by RNA interference reduced the number of ciliated cells and
increased the amount of unphosphorylated active GSK3 (see GSK3A;
606784), a key regulator of adipogenesis that is repressed by Wnt
signaling. Furthermore, differentiation of BBS10 and BBS12 patient
fibroblasts into fat-accumulating cells was associated with increased
triglyceride content compared with control cells. Marion et al. (2009)
concluded that a primary dysfunction of adipogenesis results in the
development of obesity in BBS.

ANIMAL MODEL

Kulaga et al. (2004) examined mice with deletions of the Bbs1 or Bbs4
(600374) genes. Loss of function of either BBS protein affected the
olfactory, but not the respiratory, epithelium, causing severe reduction
of the ciliated border, disorganization of the dendritic microtubule
network and trapping of olfactory ciliary proteins in dendrites and cell
bodies.

Ross et al. (2005) showed that mice with mutations in genes involved in
Bardet-Biedl syndrome share phenotypes with planar cell polarity (PCP)
mutants including open eyelids, neural tube defects, and disrupted
cochlear stereociliary bundles. Furthermore, they identified genetic
interactions between BBS genes and a PCP gene in both mouse (LTAP, also
called VANGL2; 600533) and zebrafish (vangl2). In zebrafish, the
augmented phenotype resulted from enhanced defective convergent
extension movements. Ross et al. (2005) also showed that VANGL2
localizes to the basal body and axoneme of ciliated cells, a pattern
reminiscent of that of the BBS proteins. These data suggested that cilia
are intrinsically involved in planar cell polarity processes.

Stoetzel et al. (2006) modeled loss of function of the BBS10 gene
(610148) in zebrafish. Suppression of the maternal bbs10 message caused
shortening of the rostrocaudal body axis; dorsal thinning, broadening,
and kinking of the notochord; elongation of the somites; and decreased
somitic definition and symmetry. Mild suppression of bbs10 exacerbated
the phenotypes of other bbs morphants.

Eichers et al. (2006) generated a mouse model of BBS4 by targeted
inactivation of the murine Bbs4 gene. Although the mice were initially
runted compared to wildtype, they later became obese in a
gender-dependent manner, females earlier and with more severity than
males. Blood chemistry tests indicated abnormal liver profiles, signs of
liver dysfunction, and increased insulin and leptin levels similar to
the metabolic syndrome (see 605552). Affected mice also developed
age-dependent retinal dystrophy and displayed anxiety-related behavior.
Birth defects, such an neural tube defects, occurred rarely.

Stoetzel et al. (2007) suppressed BBS6 (604896), BBS10, and BBS12
(610683) in zebrafish and observed gastrulation-movement defects
characteristic of other BBS morphants. Suppression of each of these
chaperonin-like molecules yielded highly overlapping phenotypes, but
simultaneous suppression of these 3 genes, which comprise a subfamily,
grossly exaggerated the penetrance and expressivity of these phenotypes.
Stoetzel et al. (2007) suggested that this effect might underlie either
some partial functional redundancy within the subfamily or might reflect
the progressive loss of pericentriolar function.

Davis et al. (2007) generated a knockin mouse model of the BBS1 M390R
mutation (209901.0001). Mice homozygous for M390R recapitulated aspects
of the human phenotype, including retinal degeneration, male
infertility, and obesity. Morphologic evaluation of Bbs1 mutant brain
revealed ventriculomegaly of the lateral and third ventricles, thinning
of the cerebral cortex, and reduced volume of the corpus striatum and
hippocampus. Ultrastructural examination of the ependymal cell cilia
that lined the enlarged third ventricle of Bbs1 mutant brains showed
that, whereas the 9+2 arrangement of axonemal microtubules was intact,
elongated cilia and cilia with abnormally swollen distal ends were
present. Davis et al. (2007) concluded that the M390R mutation does not
affect axonemal structure, but it may play a role in regulation of cilia
assembly and/or function.

By immunostaining for axonemal proteins, Tan et al. (2007) demonstrated
that mouse dorsal root ganglion neurons contain cilia. Bbs1-null and
Bbs4-null mice demonstrated behavioral deficits in thermosensation and
mechanosensation associated with alterations in the trafficking of the
thermosensory channel Trpv1 (602076) and the mechanosensory channel
Stoml3 (608327) within sensory neurons. The findings were replicated in
C. elegans lacking Bbs7 or Bbs8. Detailed examination of 9 patients with
BBS showed a noticeable decrease in peripheral sensation in most of
them.

Using mice lacking Bbs2, Bbs4, or Bbs6 and mice with the M390R mutation
in Bbs1, Shah et al. (2008) showed that expression of BBS proteins was
not required for ciliogenesis, but their loss caused structural defects
in a fraction of cilia covering airway epithelia. The most common
abnormality was bulges filled with vesicles near the tips of cilia, and
this same misshapen appearance was present in airway cilia from all
mutant mouse strains. Cilia of Bbs4-null and Bbs1 mutant mice beat at a
lower frequency than wildtype cilia. Neither airway hyperresponsiveness
nor inflammation increased in Bbs2- or Bbs4-null mice immunized with
ovalbumin compared with wildtype mice. Instead, mutant animals were
partially protected from airway hyperresponsiveness.

Seo et al. (2009) showed that BBS proteins were required for leptin
receptor (LEPR; 601007) signaling in the hypothalamus in mice. Bbs2 -/-,
Bbs4 -/-, and Bbs6 -/- mice were resistant to the action of leptin to
reduce body weight and food intake regardless of serum leptin (LEP;
164160) levels and obesity. Activation of hypothalamic Stat3 (102582) by
leptin was significantly decreased in Bbs2 -/-, Bbs4 -/-, and Bbs6 -/-
mice. In contrast, downstream melanocortin receptor (see 155555)
signaling was unaffected, indicating that Lepr signaling was
specifically impaired in Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice. Impaired
Lepr signaling in BBS mice was associated with decreased Pomc (176830)
gene expression. The human BBS1 protein physically interacted with LEPR,
and loss of BBS proteins perturbed LEPR trafficking in human cells. Seo
et al. (2009) concluded that BBS proteins mediate LEPR trafficking and
that impaired LEPR signaling may underlie energy imbalance in BBS.

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*FIELD* CS
INHERITANCE:
Autosomal recessive;
Digenic recessive

GROWTH:
[Other];
Obesity

HEAD AND NECK:
[Eyes];
Rod-cone dystrophy, onset by end of 2nd decade (major);
Retinitis pigmentosa;
Strabismus;
Cataracts;
[Mouth];
High arched palate;
[Teeth];
Dental crowding;
Hypodontia;
Small tooth roots

CARDIOVASCULAR:
[Heart];
Left ventricular hypertrophy;
Congenital heart defects;
Hypertension

ABDOMEN:
[Liver];
Hepatic fibrosis;
[Gastrointestinal];
Hirschsprung disease (<10%)

GENITOURINARY:
[Internal genitalia, male];
Hypogonadism (major);
[Kidneys];
Renal anomalies (major);
Nephrogenic diabetes insipidus

SKELETAL:
[Hands];
Polydactyly (major);
Brachydactyly;
[Feet];
Polydactyly (major)

NEUROLOGIC:
[Central nervous system];
Speech disorder;
Speech delay;
Learning disabilities (major);
Developmental delay;
Ataxia;
Poor coordination

MISCELLANEOUS:
Presence of 4 major features or 3 major and 2 minor features establishes
the diagnosis;
Clinical manifestation of some forms of Bardet-Biedl syndrome requires
recessive mutation in 1 of the 6 loci plus an additional mutation
in a second locus

MOLECULAR BASIS:
Caused by mutation in the BBS1 gene (BBS1, 209901.0001);
Caused by mutation in the BBS2 gene (BBS2, 606151.0001);
Caused by mutation in the ADP-ribosylation factor-like 6 gene (ARL6,
608845.0001);
Caused by mutation in the BBS4 gene (BBS4, 600374.0001);
Caused by mutation in the BBS5 gene (BBS5, 603650.0001);
Caused by mutation in the MKKS gene (MKKS, 604896.0003);
Caused by mutation in the BBS7 gene (BBS7, 607590.0001);
Caused by mutation in the tetratricopeptide repeat domain 8 gene (TTC8,
608132.0001);
Caused by mutation in the parathyroid hormone-responsive B1 gene (PTHB1,
607968.0001);
Caused by mutation in the BBS10 gene (BBS10, 610148.0001);
Caused by mutation in the tripartite-motif-containing protein 32 gene
(TRIM32, 602290.0002);
Caused by mutation in the BBS12 gene (BBS12, 610683.0001);
Caused by mutation in the MKS1 gene (MKS1, 609883.0006);
Caused by mutation in the centrosomal protein, 290kD gene (CEP290,
610142.0013);
Caused by mutation in the chromosome 2 open reading frame 86 gene
(C2orf86, 613580.0001)

*FIELD* CN
Joanna S. Amberger - updated: 8/15/2005
Joanna S. Amberger - updated: 2/27/2003
Ada Hamosh - updated: 2/14/2003
Ada Hamosh - revised: 2/26/2002

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 03/27/2012
joanna: 5/19/2011
joanna: 11/17/2010
joanna: 1/8/2010
joanna: 2/18/2009
joanna: 8/15/2005
joanna: 2/27/2003
joanna: 2/14/2003
joanna: 2/27/2002
joanna: 2/26/2002
joanna: 8/27/2001
alopez: 4/3/2001

*FIELD* CN
Ada Hamosh - updated: 11/2/2012
Cassandra L. Kniffin - updated: 5/24/2012
Ada Hamosh - updated: 1/6/2012
Cassandra L. Kniffin - updated: 7/27/2011
Cassandra L. Kniffin - updated: 4/26/2011
Cassandra L. Kniffin - updated: 3/9/2011
Cassandra L. Kniffin - updated: 2/21/2011
Cassandra L. Kniffin - updated: 12/28/2010
Cassandra L. Kniffin - updated: 11/19/2010
Marla J. F. O'Neill - updated: 9/24/2010
Patricia A. Hartz - updated: 1/20/2010
George E. Tiller - updated: 10/14/2009
Cassandra L. Kniffin - updated: 6/15/2009
Cassandra L. Kniffin - updated: 3/3/2009
Cassandra L. Kniffin - updated: 8/12/2008
Patricia A. Hartz - updated: 7/8/2008
Ada Hamosh - updated: 5/7/2008
Patricia A. Hartz - updated: 3/13/2008
Cassandra L. Kniffin - updated: 4/13/2007
Cassandra L. Kniffin - updated: 11/2/2006
Ada Hamosh - updated: 5/26/2006
Anne M. Stumpf - updated: 5/25/2006
Cassandra L. Kniffin - updated: 3/2/2006
Victor A. McKusick - updated: 10/13/2005
Victor A. McKusick - updated: 3/17/2005
Marla J. F. O'Neill - updated: 3/3/2005
Victor A. McKusick - updated: 9/10/2004
Jane Kelly - updated: 10/23/2003
Ada Hamosh - updated: 9/26/2003
Victor A. McKusick - updated: 2/27/2003
George E. Tiller - updated: 2/13/2002
Ada Hamosh - updated: 10/3/2001
George E. Tiller - updated: 7/24/2001
Michael J. Wright - updated: 10/27/1999
Michael J. Wright - updated: 6/18/1999
Victor A. McKusick - updated: 5/15/1997
Victor A. McKusick - updated: 4/14/1997
Iosif W. Lurie - updated: 8/13/1996

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
carol: 02/11/2014
carol: 11/28/2012
alopez: 11/7/2012
terry: 11/2/2012
carol: 5/31/2012
ckniffin: 5/24/2012
carol: 5/1/2012
carol: 1/6/2012
terry: 1/6/2012
alopez: 8/17/2011
ckniffin: 7/27/2011
wwang: 5/12/2011
ckniffin: 4/26/2011
wwang: 3/11/2011
ckniffin: 3/9/2011
wwang: 3/1/2011
ckniffin: 2/21/2011
wwang: 12/29/2010
ckniffin: 12/28/2010
wwang: 12/27/2010
ckniffin: 11/19/2010
alopez: 10/7/2010
alopez: 10/4/2010
wwang: 9/27/2010
terry: 9/24/2010
mgross: 1/20/2010
mgross: 10/20/2009
terry: 10/14/2009
wwang: 6/18/2009
ckniffin: 6/15/2009
wwang: 3/5/2009
ckniffin: 3/3/2009
wwang: 8/22/2008
ckniffin: 8/12/2008
mgross: 7/8/2008
alopez: 5/23/2008
terry: 5/7/2008
mgross: 3/14/2008
mgross: 3/13/2008
wwang: 4/18/2007
ckniffin: 4/13/2007
alopez: 1/4/2007
wwang: 11/7/2006
ckniffin: 11/2/2006
alopez: 6/12/2006
alopez: 6/6/2006
terry: 5/26/2006
alopez: 5/25/2006
wwang: 3/7/2006
ckniffin: 3/2/2006
alopez: 12/30/2005
alopez: 12/19/2005
alopez: 12/16/2005
alopez: 12/6/2005
alopez: 10/14/2005
terry: 10/13/2005
carol: 5/17/2005
carol: 3/28/2005
carol: 3/17/2005
terry: 3/17/2005
carol: 3/3/2005
alopez: 9/14/2004
terry: 9/10/2004
tkritzer: 8/19/2004
mgross: 6/3/2004
alopez: 4/15/2004
carol: 3/9/2004
cwells: 10/23/2003
alopez: 10/16/2003
alopez: 10/13/2003
alopez: 9/29/2003
terry: 9/26/2003
alopez: 3/4/2003
carol: 3/4/2003
tkritzer: 2/28/2003
terry: 2/27/2003
alopez: 9/16/2002
alopez: 7/18/2002
cwells: 2/18/2002
cwells: 2/13/2002
mcapotos: 12/21/2001
alopez: 10/5/2001
terry: 10/3/2001
cwells: 7/27/2001
cwells: 7/24/2001
alopez: 4/3/2001
alopez: 4/2/2001
alopez: 10/27/1999
mgross: 7/6/1999
terry: 6/18/1999
carol: 3/16/1999
dkim: 12/11/1998
dkim: 12/10/1998
alopez: 6/12/1997
alopez: 6/11/1997
alopez: 6/10/1997
jenny: 5/15/1997
terry: 5/12/1997
mark: 4/14/1997
terry: 4/10/1997
mark: 3/6/1997
carol: 8/13/1996
terry: 4/18/1996
mark: 1/16/1996
terry: 1/11/1996
mark: 3/22/1995
jason: 7/20/1994
terry: 7/19/1994
davew: 6/29/1994
mimadm: 4/29/1994
warfield: 4/14/1994

MIM 209901
*RECORD*
*FIELD* NO
209901
*FIELD* TI
*209901 BBS1 GENE; BBS1
*FIELD* TX

DESCRIPTION

BBS1 is 1 of 7 BBS proteins that form the stable core of a protein
read morecomplex required for ciliogenesis (Nachury et al., 2007).

CLONING

By positional cloning, Mykytyn et al. (2002) identified the gene that is
mutant in Bardet-Biedl syndrome-1 (see 209900). It was selected for
further examination because its encodes protein with modest similarity
to the BBS2 protein (606151). The gene consists of 3,370 bp with an open
reading frame of 593 codons. By Northern blot analysis, Mykytyn et al.
(2002) demonstrated that BBS1 was ubiquitously expressed, including
expression in fetal tissues, testis, retina, and adipose tissue. The
pattern of expression was similar to those seen for BBS2, BBS4 (600374),
and BBS6 (MKKS; 604896).

GENE STRUCTURE

Mykytyn et al. (2002) found that the BBS1 gene contains 17 exons and
spans approximately 23 kb. Mykytyn et al. (2003) showed that the BBS1
gene is highly conserved between mouse and human.

MAPPING

Mykytyn et al. (2002) identified the BBS1 gene within the critical
region defined for Bardet-Biedl syndrome-1 on chromosome 11q34.

Based on genomic sequence analysis, Sheffield (2003) assigned the mouse
Bbs1 gene to chromosome 19.

GENE FUNCTION

Nachury et al. (2007) found that BBS1, BBS2 (606151), BBS4 (600374),
BBS5 (603650), BBS7 (607590), BBS8 (TTC8; 608132), and BBS9 (607968)
copurified in stoichiometric amounts from human retinal pigment
epithelium (RPE) cells and from mouse testis. PCM1 (600299) and
alpha-tubulin (see 602529)/beta-tubulin (191130) copurified in
substoichiometric amounts. The apparent molecular mass of the complex,
which Nachury et al. (2007) called the BBSome, was 438 kD, and it had a
sedimentation coefficient of 14S. The complex localized with PCM1 to
nonmembranous centriolar satellites in the cytoplasm and, in the absence
of PCM1, to the ciliary membrane. Cotransfection and immunoprecipitation
experiments suggested that BBS9 was the complex-organizing subunit and
that BBS5 mediated binding to phospholipids, predominantly
phosphatidylinositol 3-phosphate. BBS1 mediated interaction with RABIN8
(RAB3IP; 608686), the guanine nucleotide exchange factor for the small G
protein RAB8 (RAB8A; 165040). Nachury et al. (2007) found that RAB8
promoted ciliary membrane growth through fusion of exocytic vesicles to
the base of the ciliary membrane. They concluded that BBS proteins
likely function in membrane trafficking to the primary cilium.

Loktev et al. (2008) found that BBIP10 (613605) copurified and
cosedimented with the BBS protein complex from RPE cells. Knockdown of
BBIP10 in RPE cells via small interfering RNA compromised assembly of
the BBS protein complex and caused failure of ciliogenesis. Knockdown of
BBS1, BBS5, or PCM1 resulted in a similar failure of ciliogenesis in RPE
cells. Depletion of BBIP10 or BBS8 increased the frequency of centrosome
splitting in interphase cells. BBIP10 also had roles in cytoplasmic
microtubule stabilization and acetylation that appeared to be
independent of its role in assembly of the BBS protein complex.

Using a protein pull-down assay with homogenized bovine retina, Jin et
al. (2010) showed that ARL6 (608845) bound the BBS protein complex.
Depletion of ARL6 in human RPE cells did not affect assembly of the
complex, but it blocked its localization to cilia. Targeting of ARL6 and
the protein complex to cilia required GTP binding by ARL6, but not ARL6
GTPase activity. When in the GTP-bound form, the N-terminal amphipathic
helix of ARL6 bound brain lipid liposomes and recruited the BBS protein
complex. Upon recruitment, the complex appeared to polymerize into an
electron-dense planar coat, and it functioned in lateral transport of
test cargo proteins to ciliary membranes.

Ishizuka et al. (2011) reported that phosphorylation of DISC1 (605210)
acts as a molecular switch from maintaining proliferation of mitotic
progenitor cells to activating migration of postmitotic neurons in mice.
Unphosphorylated DISC1 regulates canonical Wnt signaling via an
interaction with GSK3-beta (605004), whereas specific phosphorylation at
serine-710 triggers the recruitment of Bardet-Biedl syndrome (see
209900) proteins to the centrosome. In support of this model, loss of
BBS1 (209901) leads to defects in migration, but not proliferation,
whereas DISC1 knockdown leads to deficits in both. A phospho-dead mutant
can only rescue proliferation, whereas a phospho-mimic mutant rescues
exclusively migration defects. Ishizuka et al. (2011) concluded that
their data highlight a dual role for DISC1 in corticogenesis and
indicate that phosphorylation of this protein at serine-710 activates a
key developmental switch.

By mass spectrometric analysis of transgenic mouse testis, Seo et al.
(2011) found that Lxtfl1 (606568) copurified with human BBS4 and with
the core mouse BBS complex subunits Bbs1, Bbs2, Bbs5, Bbs7, Bbs8, and
Bbs9. Immunohistochemical analysis of human RPE cells showed
colocalization of LXTFL1 and BBS9 in cytoplasmic punctae. Use of small
interfering RNA revealed distinct functions for each BBS subunit in BBS
complex assembly and trafficking. LZTFL1 depletion and overexpression
studies showed a negative role for LZTFL1 in BBS complex trafficking,
but no effect of LZTFL1 on BBS complex assembly. Mutation analysis
revealed that the C-terminal half of Lztfl1 interacted with with the
C-terminal domain of Bbs9 and that the N-terminal half of Lztfl1
negatively regulated BBS complex trafficking. Depletion of several BBS
subunits and LZTFL1 also altered Hedgehog (SHH; 600725) signaling, as
measured by GLI1 (GLI; 165220) expression and ciliary trafficking of SMO
(SMOH; 601500).

BIOCHEMICAL FEATURES

Using computational analysis, Jin et al. (2010) found that the BBS
protein complex shares structural features with the canonical coat
complexes COPI (601924), COPII (see 610511), and clathrin AP1 (see
603531). BBS4 and BBS8 consist almost entirely of tetratricopeptide
repeats (TPRs) (13 and 12.5 TPRs, respectively), which are predicted to
fold into extended rod-shaped alpha solenoids. BBS1, BBS2, BBS7, and
BBS9 each have an N-terminal beta-propeller fold followed by an
amphipathic helical linker and a gamma-adaptin (AP1G1; 603533) ear
motif. In BBS2, BBS7, and BBS9, the ear motif is followed by an
alpha/beta platform domain and an alpha helix. In BBS1, a 4-helix bundle
is inserted between the second and third blades of the beta propeller.
BBS5 contains 2 pleckstrin (PLEK; 173570) homology domains and a 3-helix
bundle, while BBIP10 consists of 2 alpha helices. Jin et al. (2010)
concluded that the abundance of beta propellers, alpha solenoids, and
appendage domains inside the BBS protein complex suggests that it shares
an evolutionary relationship with canonical coat complexes.

MOLECULAR GENETICS

Mykytyn et al. (2002) sequenced the BBS1 gene in the probands from 6
families (5 of Puerto Rican and 1 of Turkish ancestry) showing linkage
to the BBS1 region on chromosome 11. In a consanguineous Puerto Rican
family, they found a homozygous G-to-T transversion in exon 16 that
results in a nonsense mutation, glu549 to ter (E549X; 209901.0002). In a
second consanguineous Puerto Rican family, they found a homozygous
T-to-G transversion in exon 12, predicted to result in a nonconservative
substitution from methionine to arginine at codon 390 (M390R;
209901.0001). Two additional Puerto Rican families were compound
heterozygotes with respect to the E549X and M390R mutations. Analysis of
a fifth Puerto Rican revealed the presence of a heterozygous E549X
mutation and a heterozygous G-to-A transition at the +1 position of the
splice donor site in exon 4 (432+1G-A; 209901.0003). Affected
individuals in the consanguineous Turkish family showed a homozygous
deletion of 1 bp in exon 10, resulting in a premature termination at
codon 288 (tyr284fsX288; 209901.0004). In an evaluation of 60 unrelated
North American probands with BBS of mostly northern European ancestry
for the presence of the 4 mutations identified in the extended families,
using single-strand conformation polymorphism (SSCP) analysis, Mykytyn
et al. (2002) identified 22 individuals who had at least 1 copy of the
M390R mutation. Of these 22 individuals, 16 were homozygous with respect
to this variant (allele frequency = 0.32). A sequence variant was not
detected in 192 control chromosomes from individuals of mostly northern
European ancestry.

Mykytyn et al. (2002) found that in their families with BBS1 the
disorder segregated as an autosomal recessive disease, with no evidence
of involvement of the common M390R mutation in triallelic inheritance.
See the INHERITANCE section of 209900 for a full discussion. Badano et
al. (2003) found heterozygous mutation in BBS1 (209901.0006) and
homozygous mutation in BBS7 (607590.0002) in affected individuals,
raising the possibility that BBS7 may interact genetically with other
loci to produce the BBS phenotype.

Beales et al. (2003) presented a comprehensive analysis of the spectrum,
distribution, and involvement in nonmendelian trait transmission of
mutant alleles in BBS1, the most common BBS locus. Analyses of 259
independent families segregating a BBS phenotype indicated that BBS1
participates in complex inheritance and that, in different families,
mutations in BBS1 can interact genetically with mutations at each of the
other known BBS genes, as well as genes at unknown loci, to cause the
phenotype. Consistent with this model, they identified homozygous M390R
alleles (209901.0001), the most frequent BBS1 mutation, in asymptomatic
individuals in 2 families. Moreover, their statistical analyses
indicated that the prevalence of the M390R allele in the general
population is consistent with an oligogenic rather than a recessive
model of disease transmission. Although all BBS alleles appeared to be
capable of interacting genetically with each other, some genes,
especially BBS2 and BBS6, are more likely to participate in triallelic
inheritance, suggesting a variable ability of the BBS proteins to
interact genetically with each other.

Mykytyn et al. (2003) evaluated the involvement of the BBS1 gene in a
cohort of 129 probands with BBS and reported 10 novel BBS1 mutations,
including a leu518-to-pro (L518P; 209901.0005) mutation.

ANIMAL MODEL

Davis et al. (2007) generated a knockin mouse model of the BBS1 M390R
mutation. Mice homozygous for M390R recapitulated aspects of the human
phenotype, including retinal degeneration, male infertility, and
obesity. Morphologic evaluation of Bbs1 mutant brain revealed
ventriculomegaly of the lateral and third ventricles, thinning of the
cerebral cortex, and reduced volume of the corpus striatum and
hippocampus. Ultrastructural examination of the ependymal cell cilia
that lined the enlarged third ventricle of Bbs1 mutant brains showed
that, whereas the 9+2 arrangement of axonemal microtubules was intact,
elongated cilia and cilia with abnormally swollen distal ends were
present. Davis et al. (2007) concluded that the M390R mutation does not
affect axonemal structure, but it may play a role in regulation of cilia
assembly and/or function.

Using mice lacking Bbs2, Bbs4, or Bbs6 and mice with the M390R mutation
in Bbs1, Shah et al. (2008) showed that expression of BBS proteins was
not required for ciliogenesis, but their loss caused structural defects
in a fraction of cilia covering airway epithelia. The most common
abnormality was bulges filled with vesicles near the tips of cilia, and
this same misshapen appearance was present in airway cilia from all
mutant mouse strains. Cilia of Bbs4-null and Bbs1 mutant mice beat at a
lower frequency than wildtype cilia. Neither airway hyperresponsiveness
nor inflammation increased in Bbs2- or Bbs4-null mice immunized with
ovalbumin compared with wildtype mice. Instead, mutant animals were
partially protected from airway hyperresponsiveness.

By immunostaining for axonemal proteins, Tan et al. (2007) demonstrated
that mouse dorsal root ganglion neurons contain cilia. Bbs1-null and
Bbs4-null mice demonstrated behavioral deficits in thermosensation and
mechanosensation associated with alterations in the trafficking of the
thermosensory channel Trpv1 (602076) and the mechanosensory channel
Stoml3 (608327) within sensory neurons. The findings were replicated in
C. elegans lacking Bbs7 or Bbs8 (TTC8; 608132). Detailed examination of
9 patients with BBS showed a noticeable decrease in peripheral sensation
in most of them.

*FIELD* AV
.0001
BARDET-BIEDL SYNDROME 1
BBS1, MET390ARG

Mykytyn et al. (2002) identified a met390-to-arg (M390R) mutation in the
BBS1 gene in affected members of a consanguineous Puerto Rican family
with Bardet-Biedl syndrome (209900). The substitution results from a
T-to-G transversion at nucleotide 1169 (1169T-G) in exon 12 (Mykytyn,
2002). Two other Puerto Rican families carried this mutation and the
glu549-to-ter mutation (209901.0002) in compound heterozygosity. Mykytyn
et al. (2002) found the M390R mutation in 22 of 60 unrelated North
American probands with Bardet-Biedl syndrome of mostly northern European
ancestry. Sixteen of the 22 individuals were homozygous for the variant
(allele frequency = 0.32).

Mykytyn et al. (2003) found that the M390R mutation accounts for
approximately 80% of all BBS1 mutations and is found on a similar
genetic background across populations.

Beales et al. (2003) identified homozygous M390R alleles in asymptomatic
individuals in 2 separate families. They interpreted this as consistent
with an oligogenic rather than a recessive model of disease
transmission, as seen in triallelic inheritance.

Fan et al. (2004) reported the cases of 2 sisters homozygous for the
M390R mutation. One sister, who was also heterozygous for a G169A
mutation in the BBS3 gene (600151.0002), was more severely affected than
the sister without the additional mutation, suggesting a modifying
effect of the mutation in BBS3.

.0002
BARDET-BIEDL SYNDROME 1
BBS1, GLU549TER

In a consanguineous Puerto Rican family with Bardet-Biedl syndrome
(209900), Mykytyn et al. (2002) found a homozygous G-to-T transversion
at nucleotide 1655 (1655G-T) in exon 16 of the BBS1 gene that resulted
in a glu549-to-ter (E549X) nonsense mutation.

.0003
BARDET-BIEDL SYNDROME 1
BBS1, IVS4, G-A, +1

In a Puerto Rican family with Bardet-Biedl syndrome (209900), Mykytyn et
al. (2002) found a heterozygous G-to-A transition at the +1 position of
the splice donor site in exon 4 of the BBS1 gene (432+1G-A). Affected
individuals were compound heterozygous for the E549X mutation
(209901.0002).

.0004
BARDET-BIEDL SYNDROME 1
BBS1, 1-BP DEL, 851A

In a consanguineous Turkish family with Bardet-Biedl syndrome (209900),
Mykytyn et al. (2002) found a homozygous deletion of 1 bp in exon 10 of
the BBS1 gene (851delA), resulting in premature termination at codon 288
(tyr284fsX288).

.0005
BARDET-BIEDL SYNDROME 1
BBS1, LEU518PRO

One of 10 novel mutations in the BBS1 gene reported by Mykytyn et al.
(2003) was a 1553T-C transition in exon 15 of the cDNA, resulting in a
leu518-to-pro (L518P) change. It was detected in 3 patients with
Bardet-Biedl syndrome (209900), all in combination with the M390R
mutation (209901.0001), and in none of 96 control subjects.

.0006
BARDET-BIEDL SYNDROME 7
BBS1, GLU234LYS

In a family with Bardet-Biedl syndrome (209900), Badano et al. (2003)
found a heterozygous glu234-to-lys (E234K) mutation in the BBS1 gene in
all 3 affected members. These individuals were also homozygous for a
thr211-to-ile (T211I) amino acid substitution in the BBS7 gene
(607590.0002), raising the possibility that the BBS1 and BBS7 loci
interact. Since none of the unaffected sibs was homozygous for the
defect in BBS7, it was considered equally likely that the third mutant
allele (in BBS1) is either required for pathogenesis of the BBS7
phenotype or modifies the phenotype.

.0007
BARDET-BIEDL SYNDROME 1
BBS1, 1-BP DEL, 1650C

In 2 sisters with BBS1 (209900), Badano et al. (2003) identified
compound heterozygosity for mutations in the BBS1 gene: a 1-bp deletion
in exon 16, 1650delC, resulting in a frameshift at codon 548 and a
premature stop at codon 579, and met390-to-arg (M390R; 209901.0001). The
more severely affected sister was heterozygous for a thr325-to-pro
substitution in the MKKS gene (T325P; 604896.0014).

*FIELD* RF
1. Badano, J. L.; Ansley, S. J.; Leitch, C. C.; Lewis, R. A.; Lupski,
J. R.; Katsanis, N.: Identification of a novel Bardet-Biedl syndrome
protein, BBS7, that shares structural features with BBS1 and BBS2. Am.
J. Hum. Genet. 72: 650-658, 2003.

2. Badano, J. L.; Kim, J. C.; Hoskins, B. E.; Lewis, R. A.; Ansley,
S. J.; Cutler, D. J.; Castellan, C.; Beales, P. L.; Leroux, M. R.;
Katsanis, N.: Heterozygous mutations in BBS1, BBS2 and BBS6 have
a potential epistatic effect on Bardet-Biedl patients with two mutations
at a second BBS locus. Hum. Molec. Genet. 12: 1651-1659, 2003.

3. Beales, P. L.; Badano, J. L.; Ross, A. J.; Ansley, S. J.; Hoskins,
B. E.; Kirsten, B.; Mein, C. A.; Froguel, P.; Scambler, P. J.; Lewis,
R. A.; Lupski, J. R.; Katsanis, N.: Genetic interaction of BBS1 mutations
with alleles at other BBS loci can result in non-mendelian Bardet-Biedl
syndrome. Am. J. Hum. Genet. 72: 1187-1199, 2003.

4. Davis, R. E.; Swiderski, R. E.; Rahmouni, K.; Nishimura, D. Y.;
Mullins, R. F.; Agassandian, K.; Philp, A. R.; Searby, C. C.; Andrews,
M. P.; Thompson, S.; Berry, C. J.; Thedens, D. R.; Yang, B.; Weiss,
R. M.; Cassell, M. D.; Stone, E. M.; Sheffield, V. C.: A knockin
mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia
defects, ventriculomegaly, retinopathy, and obesity. Proc. Nat. Acad.
Sci. 104: 19422-19427, 2007.

5. Fan, Y.; Esmail, M. A.; Ansley, S. J.; Blacque, O. E.; Boroevich,
K.; Ross, A. J.; Moore, S. J.; Badano, J. L.; May-Simera, H.; Compton,
D. S.; Green, J. S.; Lewis, R. A.; van Haelst, M. M.; Parfrey, P.
S.; Baillie, D. L.; Beales, P. L.; Katsanis, N.; Davidson, W. S.;
Leroux, M. R.: Mutations in a member of the Ras superfamily of small
GTP-binding proteins causes Bardet-Biedl syndrome. Nature Genet. 36:
989-993, 2004.

6. Ishizuka, K.; Kamiya, A.; Oh, E. C.; Kanki, H.; Seshadri, S.; Robinson,
J. F.; Murdoch, H.; Dunlop, A. J.; Kubo, K.; Furukori, K.; Huang,
B.; Zeledon, M.; Hayashi-Takagi, A.; Okano, H.; Nakajima, K.; Houslay,
M. D.: Katsanis, N.; Sawa, A.: DISC1-dependent switch from progenitor
proliferation to migration in the developing cortex. Nature 473:
92-96, 2011.

7. Jin, H.; White, S. R.; Shida, T.; Schulz, S.; Aguiar, M.; Gygi,
S. P.; Bazan, J. F.; Nachury, M. V.: The conserved Bardet-Biedl syndrome
proteins assemble a coat that traffics membrane proteins to cilia. Cell 141:
1208-1219, 2010.

8. Loktev, A. V.; Zhang, Q.; Beck, J. S.; Searby, C. C.; Scheetz,
T. E.; Bazan, J. F.; Slusarski, D. C.; Sheffield, V. C.; Jackson,
P. K.; Nachury, M. V.: A BBSome subunit links ciliogenesis, microtubule
stability, and acetylation. Dev. Cell 15: 854-865, 2008.

9. Mykytyn, K.: Personal Communication. Iowa City, Iowa 11/18/2002.

10. Mykytyn, K.; Nishimura, D. Y.; Searby, C. C.; Beck, G.; Bugge,
K.; Haines, H. L.; Cornier, A. S.; Cox, G. F.; Fulton, A. B.; Carmi,
R.; Iannaccone, A.; Jacobson, S. G.; and 9 others: Evaluation of
complex inheritance involving the most common Bardet-Biedl syndrome
locus (BBS1). Am. J. Hum. Genet. 72: 429-437, 2003.

11. Mykytyn, K.; Nishimura, D. Y.; Searby, C. C.; Shastri, M.; Yen,
H.; Beck, J. S.; Braun, T.; Streb, L. M.; Cornier, A. S.; Cox, G.
F.; Fulton, A. B.; Carmi, R.; Luleci, G.; Chandrasekharappa, S. C.;
Collins, F. S.; Jacobson, S. G.; Heckenlively, J. R.; Weleber, R.
G.; Stone, E. M.; Sheffield, V. C.: Identification of the gene (BBS1)
most commonly involved in Bardet-Biedl syndrome, a complex human obesity
syndrome. Nature Genet. 31: 435-438, 2002.

12. Nachury, M. V.; Loktev, A. V.; Zhang, Q.; Westlake, C. J.; Peranen,
J.; Merdes, A.; Slusarski, D. C.; Scheller, R. H.; Bazan, J. F.; Sheffield,
V. C.; Jackson, P. K.: A core complex of BBS proteins cooperates
with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129:
1201-1213, 2007.

13. Seo, S.; Zhang, Q.; Bugge, K.; Breslow, D. K.; Searby, C. C.;
Nachury, M. V.; Sheffield, V. C.: A novel protein LZTFL1 regulates
ciliary trafficking of the BBSome and Smoothened. PLoS Genet. 7:
e1002358, 2011. Note: Electronic Article.

14. Shah, A. S.; Farmen, S. L.; Moninger, T. O.; Businga, T. R.; Andrews,
M. P.; Bugge, K.; Searby, C. C.; Nishimura, D.; Brogden, K. A.; Kline,
J. N.; Sheffield, V. C.; Welsh, M. J.: Loss of Bardet-Biedl syndrome
proteins alters the morphology and function of motile cilia in airway
epithelia. Proc. Nat. Acad. Sci. 105: 3380-3385, 2008.

15. Sheffield, V. C.: Personal Communication. Iowa City, Iowa
3/6/2003.

16. Tan, P. L.; Barr, T.; Inglis, P. N.; Mitsuma, N.; Huang, S. M.;
Garcia-Gonzalez, M. A.; Bradley, B. A.; Coforio, S.; Albrecht, P.
J.; Watnick, T.; Germino, G. G.; Beales, P. L.; Caterina, M. J.; Leroux,
M. R.; Rice, F. L.; Katsanis, N.: Loss of Bardet-Biedl syndrome proteins
causes defects in peripheral sensory innervation and function. Proc.
Nat. Acad. Sci. 104: 17524-17529, 2007.

*FIELD* CN
Patricia A. Hartz - updated: 11/12/2012
Ada Hamosh - updated: 7/8/2011
Patricia A. Hartz - updated: 10/13/2010
Cassandra L. Kniffin - updated: 8/12/2008
Patricia A. Hartz - updated: 5/21/2008
Patricia A. Hartz - updated: 3/12/2008
George E. Tiller - updated: 5/24/2005
Victor A. McKusick - updated: 9/10/2004
Victor A. McKusick - updated: 6/4/2003
Victor A. McKusick - updated: 2/27/2003
Victor A. McKusick - updated: 7/16/2002
Victor A. McKusick - updated: 1/13/2000
Victor A. McKusick - updated: 12/20/1999
Michael J. Wright - updated: 6/18/1999
Victor A. McKusick - updated: 4/14/1997
Victor A. McKusick - updated: 3/6/1997

*FIELD* CD
Victor A. McKusick: 4/14/1994

*FIELD* ED
carol: 12/21/2012
mgross: 11/12/2012
alopez: 7/8/2011
mgross: 10/15/2010
terry: 10/13/2010
wwang: 8/22/2008
ckniffin: 8/12/2008
mgross: 5/21/2008
mgross: 3/14/2008
mgross: 3/13/2008
terry: 3/12/2008
tkritzer: 5/24/2005
alopez: 9/14/2004
terry: 9/10/2004
carol: 8/19/2004
cwells: 6/9/2003
terry: 6/4/2003
terry: 3/12/2003
carol: 3/6/2003
alopez: 2/28/2003
tkritzer: 2/28/2003
terry: 2/27/2003
alopez: 11/19/2002
alopez: 9/16/2002
joanna: 7/25/2002
alopez: 7/18/2002
cwells: 7/16/2002
alopez: 10/5/2001
alopez: 4/2/2001
mgross: 1/18/2000
terry: 1/13/2000
mgross: 1/11/2000
terry: 12/20/1999
mgross: 7/6/1999
terry: 6/18/1999
mark: 4/14/1997
terry: 4/10/1997
mark: 3/6/1997
terry: 3/4/1997
terry: 10/18/1994
carol: 5/12/1994
mimadm: 4/29/1994
warfield: 4/14/1994

RBCC Red Blood Cell Collection

Full text data of BBS1