RBCC

Full text data of STX16

STX16 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Syntaxin-16; Syn16

UniProt O14662
ID STX16_HUMAN Reviewed; 325 AA.
AC O14662; A6NK32; A6NN69; A8MPP0; B7ZBN1; B7ZBN2; B7ZBN3; E1P5M0;
read moreAC E1P607; O14661; O14663; O60517; Q5W084; Q5W086; Q5W087; Q5XKI6;
AC Q6GMS8; Q9H0Z0; Q9H1T7; Q9H1T8; Q9UIX5;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 24-JAN-2006, sequence version 3.
DT 22-JAN-2014, entry version 133.
DE RecName: Full=Syntaxin-16;
DE Short=Syn16;
GN Name=STX16;
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] (ISOFORMS A; B; C AND D).
RC TISSUE=Brain;
RX PubMed=9587053;
RA Simonsen A., Bremnes B., Ronning E., Aasland R., Stenmark H.;
RT "Syntaxin-16, a putative Golgi t-SNARE.";
RL Eur. J. Cell Biol. 75:223-231(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM D).
RX PubMed=9464276; DOI=10.1006/bbrc.1997.8029;
RA Tang B.L., Low D.Y.H., Lee S.S., Tan A.E.H., Ho W.;
RT "Molecular cloning and localization of human syntaxin 16, a member of
RT the syntaxin family of SNARE proteins.";
RL Biochem. Biophys. Res. Commun. 242:673-679(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS A AND E).
RC TISSUE=Kidney;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-251 (ISOFORM 6).
RC TISSUE=Placenta;
RA Li W.B., Gruber C., Jessee J., Polayes D.;
RT "Full-length cDNA libraries and normalization.";
RL Submitted (APR-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP INVOLVEMENT IN PHP1B.
RX PubMed=14561710; DOI=10.1172/JCI200319159;
RA Bastepe M., Froehlich L.F., Hendy G.N., Indridason O.S., Josse R.G.,
RA Koshiyama H., Koerkkoe J., Nakamoto J.M., Rosenbloom A.L.,
RA Slyper A.H., Sugimoto T., Tsatsoulis A., Crawford J.D., Jueppner H.;
RT "Autosomal dominant pseudohypoparathyroidism type Ib is associated
RT with a heterozygous microdeletion that likely disrupts a putative
RT imprinting control element of GNAS.";
RL J. Clin. Invest. 112:1255-1263(2003).
RN [8]
RP INVOLVEMENT IN PHP1B.
RX PubMed=15800843; DOI=10.1086/429932;
RA Linglart A., Gensure R.C., Olney R.C., Jueppner H., Bastepe M.;
RT "A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism
RT type Ib redefines the boundaries of a cis-acting imprinting control
RT element of GNAS.";
RL Am. J. Hum. Genet. 76:804-814(2005).
RN [9]
RP FUNCTION, AND INTERACTION WITH GCC2.
RX PubMed=18195106; DOI=10.1083/jcb.200707136;
RA Ganley I.G., Espinosa E., Pfeffer S.R.;
RT "A syntaxin 10-SNARE complex distinguishes two distinct transport
RT routes from endosomes to the trans-Golgi in human cells.";
RL J. Cell Biol. 180:159-172(2008).
CC -!- FUNCTION: SNARE involved in vesicular transport from the late
CC endosomes to the trans-Golgi network.
CC -!- SUBUNIT: Interacts with GCC2.
CC -!- SUBCELLULAR LOCATION: Golgi apparatus membrane; Single-pass type
CC IV membrane protein.
CC -!- SUBCELLULAR LOCATION: Isoform C: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=6;
CC Name=B;
CC IsoId=O14662-1; Sequence=Displayed;
CC Name=A;
CC IsoId=O14662-2; Sequence=VSP_006348;
CC Name=C;
CC IsoId=O14662-3; Sequence=VSP_006349, VSP_006350, VSP_006351;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=D;
CC IsoId=O14662-4; Sequence=VSP_006349;
CC Name=E;
CC IsoId=O14662-5; Sequence=VSP_043849;
CC Name=6;
CC IsoId=O14662-6; Sequence=VSP_045073;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DISEASE: Pseudohypoparathyroidism 1B (PHP1B) [MIM:603233]: A
CC disorder characterized by end-organ resistance to parathyroid
CC hormone, hypocalcemia and hyperphosphatemia. Patients affected
CC with PHP1B lack developmental defects characteristic of Albright
CC hereditary osteodystrophy, and typically show no other endocrine
CC abnormalities besides resistance to PTH. Note=The gene represented
CC in this entry is involved in disease pathogenesis. Microdeletions
CC involving STX16 can cause loss of methylation at exon A/B of GNAS,
CC resulting in PHP1B.
CC -!- SIMILARITY: Belongs to the syntaxin family.
CC -!- SIMILARITY: Contains 1 t-SNARE coiled-coil homology domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB69282.1; Type=Frameshift; Positions=142, 163, 165;
CC Sequence=AAB69283.1; Type=Frameshift; Positions=142, 163, 165;
CC Sequence=AAC05647.1; Type=Frameshift; Positions=142, 163, 165;
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DR EMBL; AF008936; AAB69283.1; ALT_FRAME; mRNA.
DR EMBL; AF008935; AAB69282.1; ALT_FRAME; mRNA.
DR EMBL; AF008937; AAB69284.1; -; mRNA.
DR EMBL; AF038897; AAC05647.1; ALT_FRAME; mRNA.
DR EMBL; AL139349; CAX14989.1; -; Genomic_DNA.
DR EMBL; AL050327; CAX14989.1; JOINED; Genomic_DNA.
DR EMBL; AL139349; CAX14990.1; -; Genomic_DNA.
DR EMBL; AL050327; CAX14990.1; JOINED; Genomic_DNA.
DR EMBL; AL139349; CAX14991.1; -; Genomic_DNA.
DR EMBL; AL050327; CAX14991.1; JOINED; Genomic_DNA.
DR EMBL; AL050327; CAI23277.1; -; Genomic_DNA.
DR EMBL; AL139349; CAI23277.1; JOINED; Genomic_DNA.
DR EMBL; AL050327; CAI23278.1; -; Genomic_DNA.
DR EMBL; AL139349; CAI23278.1; JOINED; Genomic_DNA.
DR EMBL; AL050327; CAI23279.1; -; Genomic_DNA.
DR EMBL; AL139349; CAI23279.1; JOINED; Genomic_DNA.
DR EMBL; AL050327; CAM28341.1; -; Genomic_DNA.
DR EMBL; AL139349; CAM28341.1; JOINED; Genomic_DNA.
DR EMBL; AL139349; CAX14992.1; -; Genomic_DNA.
DR EMBL; AL050327; CAX14992.1; JOINED; Genomic_DNA.
DR EMBL; CH471077; EAW75481.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75482.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75484.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75485.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75486.1; -; Genomic_DNA.
DR EMBL; BC019042; AAH19042.1; -; mRNA.
DR EMBL; BC073876; AAH73876.1; -; mRNA.
DR EMBL; BX396221; -; NOT_ANNOTATED_CDS; mRNA.
DR PIR; JC5927; JC5927.
DR RefSeq; NP_001001433.1; NM_001001433.2.
DR RefSeq; NP_001128244.1; NM_001134772.2.
DR RefSeq; NP_001128245.1; NM_001134773.2.
DR RefSeq; NP_001191797.1; NM_001204868.1.
DR RefSeq; NP_003754.2; NM_003763.5.
DR UniGene; Hs.307913; -.
DR ProteinModelPortal; O14662; -.
DR SMR; O14662; 77-292.
DR IntAct; O14662; 2.
DR MINT; MINT-1196639; -.
DR PhosphoSite; O14662; -.
DR PaxDb; O14662; -.
DR PRIDE; O14662; -.
DR DNASU; 8675; -.
DR Ensembl; ENST00000355957; ENSP00000348229; ENSG00000124222.
DR Ensembl; ENST00000358029; ENSP00000350723; ENSG00000124222.
DR Ensembl; ENST00000359617; ENSP00000352634; ENSG00000124222.
DR Ensembl; ENST00000371132; ENSP00000360173; ENSG00000124222.
DR Ensembl; ENST00000371141; ENSP00000360183; ENSG00000124222.
DR Ensembl; ENST00000467096; ENSP00000434369; ENSG00000124222.
DR GeneID; 8675; -.
DR KEGG; hsa:8675; -.
DR UCSC; uc002xzi.3; human.
DR CTD; 8675; -.
DR GeneCards; GC20P057226; -.
DR HGNC; HGNC:11431; STX16.
DR HPA; HPA041019; -.
DR HPA; HPA042033; -.
DR MIM; 603233; phenotype.
DR MIM; 603666; gene.
DR neXtProt; NX_O14662; -.
DR PharmGKB; PA36231; -.
DR eggNOG; COG5325; -.
DR HOVERGEN; HBG057612; -.
DR KO; K08489; -.
DR OMA; ANFRKKQ; -.
DR PhylomeDB; O14662; -.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_13685; Neuronal System.
DR ChiTaRS; STX16; human.
DR GeneWiki; STX16; -.
DR GenomeRNAi; 8675; -.
DR NextBio; 32541; -.
DR PRO; PR:O14662; -.
DR ArrayExpress; O14662; -.
DR Bgee; O14662; -.
DR Genevestigator; O14662; -.
DR GO; GO:0005794; C:Golgi apparatus; TAS:ProtInc.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005730; C:nucleolus; IDA:HPA.
DR GO; GO:0031201; C:SNARE complex; TAS:HGNC.
DR GO; GO:0005484; F:SNAP receptor activity; IDA:HGNC.
DR GO; GO:0006891; P:intra-Golgi vesicle-mediated transport; TAS:ProtInc.
DR GO; GO:0006886; P:intracellular protein transport; IEA:InterPro.
DR GO; GO:0042147; P:retrograde transport, endosome to Golgi; IDA:UniProtKB.
DR InterPro; IPR006012; Syntaxin/epimorphin_CS.
DR InterPro; IPR006011; Syntaxin_N.
DR InterPro; IPR010989; t-SNARE.
DR InterPro; IPR000727; T_SNARE_dom.
DR Pfam; PF05739; SNARE; 1.
DR Pfam; PF00804; Syntaxin; 1.
DR SMART; SM00397; t_SNARE; 1.
DR SUPFAM; SSF47661; SSF47661; 1.
DR PROSITE; PS00914; SYNTAXIN; 1.
DR PROSITE; PS50192; T_SNARE; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Coiled coil; Complete proteome; Cytoplasm;
KW Golgi apparatus; Membrane; Protein transport; Reference proteome;
KW Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 325 Syntaxin-16.
FT /FTId=PRO_0000210226.
FT TOPO_DOM 1 301 Cytoplasmic (Potential).
FT TRANSMEM 302 322 Helical; Anchor for type IV membrane
FT protein; (Potential).
FT TOPO_DOM 323 325 Vesicular (Potential).
FT DOMAIN 230 292 t-SNARE coiled-coil homology.
FT VAR_SEQ 1 53 Missing (in isoform 6).
FT /FTId=VSP_045073.
FT VAR_SEQ 28 48 Missing (in isoform A).
FT /FTId=VSP_006348.
FT VAR_SEQ 28 44 Missing (in isoform C and isoform D).
FT /FTId=VSP_006349.
FT VAR_SEQ 45 48 Missing (in isoform E).
FT /FTId=VSP_043849.
FT VAR_SEQ 132 132 L -> A (in isoform C).
FT /FTId=VSP_006350.
FT VAR_SEQ 133 325 Missing (in isoform C).
FT /FTId=VSP_006351.
FT CONFLICT 99 99 L -> S (in Ref. 1; AAB69282/AAB69283).
FT CONFLICT 147 147 A -> E (in Ref. 1; AAC05647).
FT CONFLICT 243 243 I -> M (in Ref. 1; AAB69282/AAB69283).
SQ SEQUENCE 325 AA; 37031 MW; 65F566541A042C3C CRC64;
MATRRLTDAF LLLRNNSIQN RQLLAEQVSS HITSSPLHSR SIAAELDELA DDRMALVSGI
SLDPEAAIGV TKRPPPKWVD GVDEIQYDVG RIKQKMKELA SLHDKHLNRP TLDDSSEEEH
AIEITTQEIT QLFHRCQRAV QALPSRARAC SEQEGRLLGN VVASLAQALQ ELSTSFRHAQ
SGYLKRMKNR EERSQHFFDT SVPLMDDGDD NTLYHRGFTE DQLVLVEQNT LMVEEREREI
RQIVQSISDL NEIFRDLGAM IVEQGTVLDR IDYNVEQSCI KTEDGLKQLH KAEQYQKKNR
KMLVILILFV IIIVLIVVLV GVKSR
//

MIM 603233
*RECORD*
*FIELD* NO
603233
*FIELD* TI
#603233 PSEUDOHYPOPARATHYROIDISM, TYPE IB; PHP1B
;;PHP IB
*FIELD* TX
A number sign (#) is used with this entry because
read morepseudohypoparathyroidism type Ib (PHP Ib) is caused by deletions in the
differentially methylated region (DMR) of the GNAS (139320) locus. One
deletion (139320.0031) removes the entire NESP55 DMR and exons 3 and 4
of the antisense transcript of the GNAS gene (GNASAS; 610540.0001).
PHP1B can also result from deletion in the STX gene (603666), a
long-range control element of methylation at the GNAS locus. These
methylation and imprinting defects result in the absence of expression
of the maternal Gs-alpha isoform.

DESCRIPTION

Pseudohypoparathyroidism refers to a heterogeneous group of disorders
characterized by resistance to parathyroid hormone (PTH; 168450).
Pseudohypoparathyroidism type Ib is characterized clinically by isolated
renal PTH resistance manifest as hypocalcemia, hyperphosphatemia, and
increased serum PTH. Biochemical studies show a decreased response of
urinary cAMP to exogenous PTH, but normal Gs activity in erythrocytes
because the defect is restricted to renal tubule cells. In contrast to
the findings in PHP Ia, patients with PHP Ib usually lack the physical
characteristics of Albright hereditary osteodystrophy (AHO) and
typically show no other endocrine abnormalities, although resistance to
thyroid-stimulating hormone (TSH; 188540) has been reported in PHP Ib
(Levine et al., 1983, Heinsimer et al., 1984). However, patients with
PHP Ib may rarely show some features of AHO (Mariot et al., 2008).

For a general phenotypic description, classification, and a discussion
of molecular genetics of pseudohypoparathyroidism, see PHP1A (103580).

CLINICAL FEATURES

Frame et al. (1972) reported 2 patients with renal resistance to
parathyroid hormone characterized by hypocalcemia and hyperphosphatemia
and associated with osteitis fibrosa cystica. Frame et al. (1972)
postulated that renal PTH resistance was the primary defect and that a
secondary hyperparathyroid state occurred to cause the skeletal changes
of osteitis fibrosa. The calcemic effect of both endogenous and
exogenous PTH was blunted by the presence of hyperphosphatemia.

Farfel and Bourne (1980) reported a family in which 5 patients with PHP
type I had no signs of AHO and showed normal erythrocyte Gs protein
activity.

Kidd et al. (1980) described 3 patients with PHP and bone findings
consistent with hyperparathyroidism, including elevated serum alkaline
phosphatase and subperiosteal resorption on skeletal films. None of the
patients had AHO features of short stature, brachydactyly, or mental
deficiency. The authors commented on the paradoxic occurrence of
hyperparathyroid bone disease in PHP, and suggested that this was an
extreme of a clinical spectrum of skeletal responsiveness to excess PTH.

Heinsimer et al. (1984) found that beta-adrenergic agonist-specific
binding properties of red cell membranes were 45% of controls in 5
patients with PHP Ia and 97% of controls in 5 patients with PHP Ib.
Further studies were consistent with a single defect causing deficient
hormone receptor-nucleotide complex formation and adenylate cyclase
activity in PHP Ia, whereas the biochemical lesion(s) appeared not to
affect the complex formation in PHP Ib.

Liu et al. (2000) studied 13 patients with PHP Ib, all of whom initially
presented with hypocalcemia, hyperphosphatemia, and elevated serum PTH
levels in the absence of renal insufficiency or any of the clinical or
radiologic features of Albright hereditary osteodystrophy. Serum
thyrotropin (TSH), thyroxine (T4), free T4, triiodothyronine (T3), and
25-hydroxyvitamin D levels were normal in all patients. Two patients had
overt osteitis fibrosa cystica at presentation that resolved with oral
calcium and vitamin D therapy. Two other patients had at least 1 other
affected family member.

- Clinical Variability

De Nanclares et al. (2007) reported 4 unrelated patients who were
thought to have PHP1A because of PTH and TSH resistance and mild
features of Albright hereditary osteodystrophy. Two patients showed
decreased G-alpha activity in erythrocytes. However, genetic analysis
did not reveal germline point mutations in the GNAS gene in any of the
patients; instead, all were found to have GNAS methylation defects,
which are usually associated with PHP1B. Furthermore, 1 of the patients
with normal G-alpha activity was found to have a 3.0-kb STX16 deletion
(603666.0001), which is usually associated with PHP1B. The findings
suggested that there may be an overlap between the molecular and
clinical features of PHP1A and PHP1B, and that methylation defects may
manifest as mild PHP1A.

Mariot et al. (2008) reported a girl with obvious Albright
osteodystrophy features, PTH resistance, and normal G-alpha-s
bioactivity in red blood cells (PHP Ib), yet no loss-of-function
mutation in the GNAS coding sequence. The patient had broad methylation
changes at all differentially methylated regions of the GNAS gene
leading to a paternal epigenotype on both alleles. Mariot et al. (2008)
suggested that Albright osteodystrophy features are not specific to PHP
Ia, and concluded that the decreased expression of G-alpha-s due to GNAS
epimutations is not restricted to the renal tubule but may affect
nonimprinted tissues like bone. PHP1B should be considered a
heterogeneous disorder that should lead to the study of GNAS epigenotype
in patients with PHP and no mutation in GNAS exons 1 through 13,
regardless of their physical features.

Lecumberri et al. (2010) reported a patient with PHP1B who had paternal
uniparental isodisomy of chromosome 20q. However, he also had mild
features of AHO and cognitive impairment, suggestive of PHP1A.
Erythrocyte Gs-alpha activity was slightly decreased at 81% of control
values.

INHERITANCE

PHP Ib is most often a sporadic disorder, but sex-influenced autosomal
dominant inheritance has been reported. In familial cases, PTH
resistance in PHP1B develops only after maternal inheritance of the
molecular defect, whereas paternal inheritance of the defect is not
associated with PTH resistance. This is the same situation as in PHP1A
and PPHP (612463) (Mantovani and Spada, 2006).

By analysis of 4 families with PHP1B, Juppner et al. (1998) showed that
the genetic defect is imprinted paternally, meaning that the disorder
only occurs if the defective gene is inherited from a female carrier.
Offspring of an affected father were unaffected.

Lecumberri et al. (2010) reported 2 unrelated families in which PHP1A
and PHP1B occurred coincidentally within different branches of each of
the families. In the first family, 2 sibs with PHP1A inherited a GNAS
mutation from their affected mother. A man from another branch of the
family with PHP1B was found to have paternal uniparental isodisomy of
chromosome 20q, with presumed lack of expression of the maternal allele.
The diagnosis was confusing in this patient before molecular analysis
because he had mild features of AHO and cognitive impairment, suggestive
of PHP1A. Genetic analysis confirmed that he did not have a germline
GNAS mutation. In the second family, 1 individual with PHP1A had a GNAS
mutation (139320.0011) inherited from his mother, and a second cousin
had PHP1B with an epigenetic defect at the GNAS locus. Lecumberri et al.
(2010) emphasized the importance of molecular diagnosis for proper
genetic counseling.

MAPPING

Juppner et al. (1998) performed a genomewide search using genomic DNA
from 4 kindreds with PHP Ib and established linkage to a small telomeric
region on chromosome 20q (20q13.3), which contains the GNAS1 gene.
However, no gross deletions or rearrangements of the GNAS gene were
detected by Southern blot analysis. Juppner et al. (1998) postulated
that mutations in a promoter or enhancer of the GNAS gene could explain
the kidney-specific resistance toward PTH and the resulting hypocalcemia
in patients with PHP Ib.

PATHOGENESIS

PHP Ib is caused by methylation and imprinting defects of the maternal
GNAS gene with subsequent loss of expression of the Gs-alpha protein in
renal proximal tubules. Since only the maternal allele, and not the
paternal allele, is expressed in renal tubule cells, the defect results
in complete lack of Gs-alpha activity in these cells. Patients with
PHP1B do not have mutations within GNAS exons that encode the Gs-alpha
isoform (Mantovani and Spada, 2006; Bastepe, 2008).

Hayward et al. (1998) found that a splice variant of the GNAS1 gene,
XL-alpha-s (Kehlenbach et al., 1994), is transcribed from the paternal
allele only, providing further confirmation that the chromosomal region
that comprises the GNAS locus undergoes imprinting. The authors noted
that if GNAS transcripts are derived, at least in some tissues or cells,
from only 1 parental allele, mutations in a promoter or enhancer of the
GNAS gene could explain the kidney-specific resistance toward PTH and
hypocalcemia in patients with PHP Ib.

Zheng et al. (2001) noted that kindred studies in PHP Ib suggested that
the cause of isolated renal resistance to PTH is a specific decrease in
Gs-alpha activity in renal proximal tubules due to paternal imprinting
of Gs-alpha. However, using RT-PCR assays, Zheng et al. (2001) found
that Gs-alpha transcripts were biallelically expressed in human fetal
kidney cortex. The results were in contrast to the parent-specific
expression of exon 1A and XL-alpha-s (paternal) or NESP (maternal)
mRNAs. The authors concluded that PHP1B is not due to paternal
imprinting of Gs-alpha within the renal proximal tubule, and proposed
that maternal inheritance of abnormal imprinting of upstream GNAS1 exons
might be responsible for PHP1B. However, Liu et al. (2000) stated that
Gs-alpha is biallelically expressed in all fetal tissues.

Using hot-stop PCR analysis on total RNA from 6 normal human thyroid
specimens, Liu et al. (2003) showed that the majority of the Gs-alpha
mRNA (72 +/- 3%) was derived from the maternal allele. Patients with PHP
Ib have an imprinting defect of the Gs-alpha gene resulting in both
alleles having a paternal epigenotype, which would lead to a more
moderate level of thyroid-specific Gs-alpha deficiency. The authors
found evidence of borderline TSH resistance in 10 of 22 PHP Ib patients.
The authors concluded that their study provided further evidence for
tissue-specific imprinting of Gs-alpha in humans with a potential
mechanism for borderline TSH resistance in some patients with PHP Ib.

MOLECULAR GENETICS

Liu et al. (2000) showed that the human GNAS exon 1A promoter region,
located 2.5 kb upstream from exon 1 of the Gs-alpha transcript, is
within a differentially methylated region (DMR) and is imprinted in a
manner similar to that in the mouse: the region is normally methylated
on the maternal allele and unmethylated on the paternal allele. In 13
patients with PHP1B, Liu et al. (2000) found that the exon 1A region of
GNAS was unmethylated on both alleles, consistent with an imprinting
defect. The authors proposed that the exon 1A DMR is important for
establishing or maintaining tissue-specific imprinting of Gs-alpha, and
that paternal-specific imprinting of exon 1A on both alleles would
reduce Gs-alpha expression specifically in renal proximal tubules, which
only express Gs-alpha from the maternal allele.

In affected individuals in 9 unrelated kindreds with PHP Ib, Bastepe et
al. (2001) found loss of methylation at GNAS1 exon 1A, which they called
exon A/B. Further genetic analysis of the largest PHP Ib kindred
revealed that the mutation leading to the disease, and presumably to the
methylation defect at exon 1A, most likely resided in untranscribed
GNAS1 sequences 56 kb centromeric to exon 1A.

Bastepe et al. (2001) reported a patient with PHP Ib who had paternal
uniparental isodisomy of chromosome 20q and lacked the maternal-specific
methylation pattern within GNAS1. There was no impairment of Gs-alpha
activity in fibroblasts. The authors suggested that loss of the maternal
GNAS1 gene and the resulting epigenetic changes alone could lead to PTH
resistance in the proximal renal tubules.

Jan de Beur et al. (2003) analyzed allelic expression and epigenetic
methylation of CpG islands within exon 1A of GNAS1 in patients with
sporadic PHP Ib and in affected and unaffected individuals from 5
multigenerational kindreds with familial PHP Ib. All subjects with
PTH-resistance showed loss of methylation of the exon 1A region on the
maternal GNAS1 allele and/or biallelic expression of exon 1A-containing
transcripts, consistent with an imprinting defect. Paternal transmission
of the disease-associated haplotype was associated with normal patterns
of GNAS1 methylation and PTH responsiveness. In 1 kindred, affected and
unaffected sibs had inherited the same GNAS1 allele from their affected
mother, indicating dissociation between the genetic and epigenetic GNAS1
defects. The absence of the epigenetic defect in subjects who inherited
a defective maternal GNAS1 allele suggested that the genetic mutation
may be incompletely penetrant and indicated that the epigenetic defect,
not the genetic mutation, leads to renal resistance to PTH in PHP Ib.

In affected members and obligate carriers of 12 unrelated families with
PHP Ib, Bastepe et al. (2003) identified a heterozygous 3-kb
microdeletion located approximately 220 kb centromeric of exon 1A of the
GNAS gene. The deletion also included 3 of 8 exons encoding syntaxin-16
(603666.0001). However, Bastepe et al. (2003) considered the involvement
of STX16 in the molecular pathogenesis of PHP Ib unlikely. They
postulated that the microdeletion disrupts a putative cis-acting element
required for methylation at exon 1A in the GNAS locus, and that this
genetic defect underlies the pathogenesis of PHP Ib. Four of 16
apparently sporadic patients also had the deletion. Affected individuals
with the microdeletion showed loss of exon 1A methylation, but no other
epigenetic abnormalities. In all examined cases, the deletion was
inherited from the mother, consistent with the observation that PHP Ib
develops only in offspring of female obligate carriers.

In all affected individuals and obligate carriers in a large kindred
with PHP Ib, Linglart et al. (2005) identified a 4.4-kb microdeletion
overlapping with a region of the 3-kb deletion identified by Bastepe et
al. (2003). Affected individuals exhibited loss of methylation only at
GNAS exon A/B. Linglart et al. (2005) concluded that PHP Ib comprises at
least 2 distinct conditions sharing the same clinical phenotype: one
associated with the loss of exon A/B methylation alone and, in most
cases, with a heterozygous microdeletion in the STX16 region, and the
other associated with methylation abnormalities at all GNAS DMRs,
including the DMR at exon A/B.

Among 20 unrelated PHP Ib probands, Liu et al. (2005) found that all had
loss of GNAS exon 1A imprinting (a paternal epigenotype on both
alleles). All 5 probands with familial disease had a deletion mutation
within the closely linked STX16 gene and a GNAS imprinting defect
involving only the exon 1A region. In contrast, the STX16 mutation was
absent in all sporadic cases. The majority of these patients had
abnormal imprinting of the more upstream regions in addition to the exon
1A imprinting defect, with 8 of 15 having a paternal epigenotype on both
alleles throughout the GNAS locus. In virtually all cases, the
imprinting status of the paternally methylated NESP55 and maternally
methylated NESPAS/XL-alpha-s promoters was concordant, suggesting that
their imprinting may be coregulated, whereas the imprinting of the
NESPAS/XL-alpha-s promoter region and XL-alpha-s first exon was not
always concordant, even though they are closely linked and lie within
the same DMR. The authors concluded that familial and sporadic forms of
PHP Ib have distinct GNAS imprinting patterns that occur through
different defects in the imprinting mechanism.

In affected members of 2 unrelated kindreds with PHP Ib who lacked STX16
mutations or deletions, Bastepe et al. (2005) identified heterozygosity
for a 4.7-kb deletion that removed the DMR of the GNAS gene encompassing
the NESP55 region and exons 3 and 4 of the GNAS antisense transcript
(GNASAS) (see 139320.0031 and 610540.0001). When inherited from a
female, the deletion abolished all maternal GNAS imprints and
derepressed maternally silenced transcripts, suggesting that the deleted
region contains a cis-acting element that controls imprinting of the
maternal GNAS allele.

Mantovani et al. (2007) studied GNAS differential methylation and STX16
microdeletions in genomic DNA from 10 Italian patients with sporadic PHP
Ib. Molecular analysis showed GNAS cluster imprinting defects in all of
the patients, only one of whom had a de novo STX16 deletion. All of the
patients were resistant to TSH, and all but 1 maintained normal
responsiveness to GHRH.

- Variability

In 3 brothers with a clinical diagnosis of PHP Ib, Wu et al. (2001)
identified heterozygosity for a 3-bp in-frame deletion in exon 13 of the
GNAS gene (ile382del; 139320.0033), resulting in an amino acid change in
the C terminus of the protein. The boys had hypocalcemia, increased
serum PTH, lack of cAMP response to PTH, and normal erythrocyte Gs
activity. When expressed in vitro, the mutant Gs-alpha was unable to
interact with the PTH receptor (PTHR1; 168468) but showed normal
coupling to other coexpressed heptahelical receptors. The findings were
consistent with isolated PTH resistance. Although the mother and
maternal grandfather also carried the mutation, they had no evidence of
PTH resistance, consistent with a model of paternal imprinting of the
locus.

Linglart et al. (2002) identified a heterozygous nonsense mutation in
exon 13 of the GNAS gene (Y391X; 139320.0036) in a girl with a clinical
diagnosis of PHP1C (612462). She had PTH resistance, multiple hormone
resistance, and the physical features of Albright hereditary
osteodystrophy. Biochemical studies showed decreased cAMP response to
PTH and normal erythrocyte cAMP activity. The mutation terminated the
Gs-alpha isoform only 4 amino acids before the wildtype stop codon, and
was shown to interrupt receptor coupling while retaining adenylyl
cyclase activity. The retention of erythrocyte Gs-alpha activity and
lack of cAMP response to PTH associated with a mutation in the
C-terminal receptor-coupling domain of Gs-alpha was similar to that
observed in the patient reported by Wu et al. (2001).

HISTORY

Although the selective resistance toward a single hormone (PTH) in PHP
Ib suggested inactivating mutations in the receptor for PTH, a
considerable number of PHP Ib patients were found to have no mutations
in the coding or noncoding exons of the PTHR1 (168468) gene (Schipani et
al., 1995; Bettoun et al., 1997). Furthermore, analysis of PTHR1 mRNA
provided no evidence for splice variants that could have offered an
explanation for the disorder (Suarez et al., 1995). Inactivating
mutations in the PTHR1 gene were found in patients with the Blomstrand
type of lethal metaphyseal chondrodysplasia (215045).

Fukumoto et al. (1996) reported reduced expression of the 2.4-kb
PTH/PTHrP receptor mRNA in 2 patients with PHP type Ib and higher levels
in a third. Reduced expression was also reported by Suarez et al.
(1995). Fukumoto et al. (1996) suggested that while lower levels of
PTH/PTHrP receptor transcript may explain the resistance to PTH in some
PHP type Ib patients, this cannot be a general mechanism.

Jan de Beur et al. (2000) used polymorphic markers in or near the genes
encoding PTH and its receptors to perform linkage analysis between these
loci and PHP1B. They found no linkage between the PTH gene or the PTH
receptor genes and PHP1B.

*FIELD* RF
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Azuma, Y.; Kruse, K.; Rosenbloom, A. L.; Koshiyama, H.; Juppner, H.
: Positional dissociation between the genetic mutation responsible
for pseudohypoparathyroidism type Ib and the associated methylation
defect at exon A/B: evidence for a long-range regulatory element within
the imprinted GNAS1 locus. Hum. Molec. Genet. 10: 1231-1241, 2001.

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A. L.; Slyper, A. H.; Sugimoto, T.; Tsatsoulis, A.; Crawford, J. D.;
Juppner, H.: Autosomal dominant pseudohypoparathyroidism type Ib
is associated with a heterozygous microdeletion that likely disrupts
a putative imprinting control element of GNAS. J. Clin. Invest. 112:
1255-1263, 2003.

4. Bastepe, M.; Frohlich, L. F.; Linglart, A.; Abu-Zahra, H. S.; Tojo,
K.; Ward, L. M.; Juppner, H.: Deletion of the NESP55 differentially
methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism
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5. Bastepe, M.; Lane, A. H.; Juppner, H.: Parental uniparental isodisomy
of chromosome 20q--and the resulting changes in GNAS1 methylation--as
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6. Bettoun, J. D.; Minagawa, M.; Kwan, M. Y.; Lee, H. S.; Yasuda,
T.; Hendy, G. N.; Goltzman, D.; White, J. H.: Cloning and characterization
of the promoter regions of the human parathyroid hormone (PTH)/PTH-related
peptide receptor gene: analysis of deoxyribonucleic acid from normal
subjects and patients with pseudohypoparathyroidism type 1b. J. Clin.
Endocr. Metab. 82: 1031-1040, 1997.

7. de Nanclares, G. P.; Fernandez-Rebollo, E.; Santin, I.; Garcia-Cuartero,
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J. R.; Barros, F.; Zazo, N.; Ahrens, W.; Juppner, H.; Hiort, O.; Castano,
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and mild features of Albright's hereditary osteodystrophy. J. Clin.
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8. Farfel, Z.; Bourne, H. R.: Deficient activity of receptor-cyclase
coupling protein in platelets of patients with pseudohypoparathyroidism. J.
Clin. Endocr. Metab. 51: 1202-1204, 1980.

9. Frame, B.; Hanson, C. A.; Frost, H. M.; Block, M.; Arnstein, A.
R.: Renal resistance to parathyroid hormone with osteitis fibrosa:
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10. Fukumoto, S.; Suzawa, M.; Takeuchi, Y.; Kodama, Y.; Nakayama,
K.; Ogata, E.; Matsumoto, T.; Fujita, T.: Absence of mutations in
parathyroid hormone (PTH)/PTH-related protein receptor complementary
deoxyribonucleic acid in patients with pseudohypoparathyroidism type
Ib. J. Clin. Endocr. Metab. 81: 2554-2558, 1996.

11. Hayward, B.; Kamiya, M.; Takada, S.; Moran, V.; Strain, L.; Hayashizaki,
Y.; Bonthron, D. T.: XL alpha s is a paternally derived protein product
of the human GNAS1 gene. (Abstract) Europ. J. Hum. Genet. 6 (suppl.
1): 36 only, 1998.

12. Heinsimer, J. A.; Davies, A. O.; Downs, R. W.; Levine, M. A.;
Spiegel, A. M.; Drezner, M. K.; De Lean, A.; Wreggett, K. A.; Caron,
M. G.; Lefkowitz, R. J.: Impaired formation of beta-adrenergic receptor-nucleotide
regulatory protein complexes in pseudohypoparathyroidism. J. Clin.
Invest. 73: 1335-1343, 1984.

13. Jan de Beur, S.; Ding, C.; Germain-Lee, E.; Cho, J.; Maret, A.;
Levine, M. A.: Discordance between genetic and epigenetic defects
in pseudohypoparathyroidism type 1b revealed by inconsistent loss
of maternal imprinting at GNAS1. Am. J. Hum. Genet. 73: 314-322,
2003.

14. Jan de Beur, S. M.; Ding, C.-L.; LaBuda, M. C.; Usdin, T. B.;
Levine, M. A.: Pseudohypoparathyroidism 1b: exclusion of parathyroid
hormone and its receptors as candidate disease genes. J. Clin. Endocr.
Metab. 85: 2239-2246, 2000.

15. Juppner, H.; Schipani, E.; Bastepe, M.; Cole, D. E. C.; Lawson,
M. L.; Mannstadt, M.; Hendy, G. N.; Plotkin, H.; Koshiyama, H.; Koh,
T.; Crawford, J. D.; Olsen, B. R.; Vikkula, M.: The gene responsible
for pseudohypoparathyroidism type Ib is paternally imprinted and maps
in four unrelated kindreds to chromosome 20q13.3. Proc. Nat. Acad.
Sci. 95: 11798-11803, 1998.

16. Kehlenbach, R. H.; Matthey, J.; Huttner, W. B.: XL alpha S is
a new type of G protein. Nature 372: 804-809, 1994. Note: Erratum:
Nature 375: 253 only, 1995.

17. Kidd, G. S.; Schaaf, M.; Adler, R. A.; Lassman, M. N.; Wray, H.
L.: Skeletal responsiveness in pseudohypoparathyroidism: a spectrum
of clinical disease. Am. J. Med. 68: 772-781, 1980.

18. Lecumberri, B.; Fernandez-Rebollo, E.; Sentchordi, L.; Saavedra,
P.; Bernal-Chico, A.; Pallardo, L. F.; Bustos, J. M. J.; Castano,
L.; de Santiago, M.; Hiort, O.; Perez de Nanclares, G.; Bastepe, M.
: Coexistence of two different pseudohypoparathyroidism subtypes (Ia
and Ib) in the same kindred with independent Gs-alpha coding mutations
and GNAS imprinting defects. J. Med. Genet. 47: 276-280, 2010.

19. Levine, M. A.; Downs, R. W., Jr.; Moses, A. M.; Breslau, N. A.;
Marx, S. J.; Lasker, R. D.; Rizzoli, R. E.; Aurbach, G. D.; Spiegel,
A. M.: Resistance to multiple hormones in patients with pseudohypoparathyroidism:
association with deficient activity of guanine nucleotide regulatory
protein. Am. J. Med. 74: 545-556, 1983.

20. Linglart, A.; Carel, J. C.; Garabedian, M.; Le, T.; Mallet, E.;
Kottler, M. L.: GNAS1 lesions in pseudohypoparathyroidism Ia and
Ic: genotype phenotype relationship and evidence of the maternal transmission
of the hormonal resistance. J. Clin. Endocr. Metab. 87: 189-197,
2002.

21. Linglart, A.; Gensure, R. C.; Olney, R. C.; Juppner, H.; Bastepe,
M.: A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism
type Ib redefines the boundaries of a cis-acting imprinting control
element of GNAS. Am. J. Hum. Genet. 76: 804-814, 2005. Note: Erratum:
Am. J. Hum. Genet. 81: 196 only, 2007.

22. Liu, J.; Erlichman, B.; Weinstein, L. S.: The stimulatory G protein
alpha-subunit Gs-alpha is imprinted in human thyroid glands: implications
for thyroid function in pseudohypoparathyroidism types 1A and 1B. J.
Clin. Endocr. Metab. 88: 4336-4341, 2003.

23. Liu, J.; Litman, D.; Rosenberg, M. J.; Yu, S.; Biesecker, L. G.;
Weinstein, L. S.: A GNAS1 imprinting defect in pseudohypoparathyroidism
type IB. J. Clin. Invest. 106: 1167-1174, 2000.

24. Liu, J.; Nealon, J. G.; Weinstein, L. S.: Distinct patterns of
abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism
type IB. Hum. Molec. Genet. 14: 95-102, 2005.

25. Mantovani, G.; Bondioni, S.; Linglart, A.; Maghnie, M.; Cisternino,
M.; Corbetta, S.; Lania, A. G.; Beck-Peccoz, P.; Spada, A.: Genetic
analysis and evaluation of resistance to thyrotropin and growth hormone-releasing
hormone in pseudohypoparathyroidism type Ib. J. Clin. Endocr. Metab. 92:
3738-3742, 2007.

26. Mantovani, G.; Spada, A.: Mutations in the Gs alpha gene causing
hormone resistance. Best Prac. Res. Clin. Endocr. Metab. 20: 501-513,
2006.

27. Mariot, V.; Maupetit-Mehouas, S.; Sinding, C.; Kottler, M.-L.;
Linglart, A.: A maternal epimutation of GNAS leads to Albright osteodystrophy
and parathyroid hormone resistance. J. Clin. Endocr. Metab. 93:
661-665, 2008.

28. Schipani, E.; Weinstein, L. S.; Bergwitz, C.; Iida-Klein, A.;
Kong, X. F.; Stuhrmann, M.; Kruse, K.; Whyte, M. P.; Murray, T.; Schmidtke,
J.; van Dop, C.; Brickman, A. S.; Crawford, J. D.; Potts, J. T., Jr.;
Kronenberg, H. M.; Abou-Samra, A. B.; Segre, G. V.; Juppner, H.:
Pseudo hypoparathyroidism type Ib is not caused by mutation in the
coding exons of the human parathyroid hormone (PTH)/PTH-related peptide
receptor gene. J. Clin. Endocr. Metab. 80: 1611-1621, 1995.

29. Suarez, F.; Lebrun, J. J.; Lecossier, D.; Escoubet, B.; Coureau,
C.; Silve, C.: Expression and modulation of the parathyroid hormone
(PTH)/PTH-related peptide receptor messenger ribonucleic acid in skin
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Clin. Endocr. Metab. 80: 965-970, 1995.

30. Wu, W.-I.; Schwindinger, W. F.; Aparicio, L. F.; Levine, M. A.
: Selective resistance to parathyroid hormone caused by a novel uncoupling
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165-171, 2001.

31. Zheng, H.; Radeva, G.; McCann, J. A.; Hendy, G. N.; Goodyer, C.
G.: G-alpha-s transcripts are biallelically expressed in the human
kidney cortex: implications for pseudohypoparathyroidism type 1b. J.
Clin. Endocr. Metab. 86: 4627-4629, 2001.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKELETAL:
Osteitis fibrosa cystica due to elevated parathyroid hormone (PTH)
(subset of patients)

ENDOCRINE FEATURES:
Renal resistance to PTH;
Pseudohypoparathyroidism

LABORATORY ABNORMALITIES:
Elevated serum PTH;
Hypocalcemia;
Hyperphosphatemia;
Normal erythrocyte Gs activity;
Low urinary cyclic AMP response to PTH administration

MISCELLANEOUS:
Many cases result from de novo mutations;
Endocrine abnormalities confined to kidney;
Typically no physical features of Albright hereditary osteodystrophy
(AHO);
Features of AHO may rarely be observed, including brachydactyly, short
metacarpals, and obesity (see 103580);
Associated with imprinting and epigenetic defects in the G-protein,
alpha-stimulating 1 gene (GNAS1, 139320);
See also pseudohypoparathyroidism type Ia (PHP1A, 103580)

MOLECULAR BASIS:
Caused by mutation in the GNAS complex locus gene (GNAS, 139320.0031);
Caused by mutation in the GNAS complex locus, antisense transcript
(GNASAS, 610540.0001);
Caused by mutation in the syntaxin 16 gene (STX16, 603666.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 5/18/2009
Cassandra L. Kniffin - updated: 12/15/2008

*FIELD* CD
Cassandra L. Kniffin: 8/25/2003

*FIELD* ED
joanna: 05/25/2012
joanna: 5/19/2011
ckniffin: 5/18/2009
joanna: 12/30/2008
ckniffin: 12/15/2008
ckniffin: 8/25/2003

*FIELD* CN
Cassandra L. Kniffin - updated: 5/28/2010
Cassandra L. Kniffin - updated: 2/5/2009
John A. Phillips, III - updated: 3/21/2008
George E. Tiller - updated: 10/31/2007
Marla J. F. O'Neill - updated: 11/8/2006
John A. Phillips, III - updated: 7/8/2005
Victor A. McKusick - updated: 3/16/2005
Cassandra L. Kniffin - updated: 11/10/2003
Cassandra L. Kniffin - reorganized: 8/27/2003
Victor A. McKusick - updated: 8/11/2003
Victor A. McKusick - updated: 5/9/2003
John A. Phillips, III - updated: 3/22/2002
Victor A. McKusick - updated: 6/15/2001
John A. Phillips, III - updated: 2/12/2001

*FIELD* CD
Victor A. McKusick: 10/28/1998

*FIELD* ED
terry: 03/14/2013
wwang: 6/2/2010
ckniffin: 5/28/2010
ckniffin: 5/18/2009
alopez: 4/24/2009
wwang: 2/10/2009
ckniffin: 2/5/2009
carol: 12/19/2008
ckniffin: 12/15/2008
carol: 3/21/2008
alopez: 11/5/2007
alopez: 11/2/2007
terry: 10/31/2007
carol: 6/29/2007
wwang: 11/8/2006
mgross: 11/1/2006
alopez: 7/8/2005
wwang: 6/27/2005
carol: 6/24/2005
carol: 3/16/2005
tkritzer: 11/17/2003
ckniffin: 11/10/2003
carol: 8/27/2003
ckniffin: 8/22/2003
tkritzer: 8/15/2003
terry: 8/11/2003
carol: 5/13/2003
tkritzer: 5/13/2003
terry: 5/9/2003
alopez: 10/10/2002
alopez: 3/22/2002
cwells: 6/27/2001
terry: 6/15/2001
mgross: 3/1/2001
terry: 2/12/2001
carol: 12/13/1998
carol: 11/13/1998
dkim: 11/13/1998
carol: 10/29/1998

MIM 603666
*RECORD*
*FIELD* NO
603666
*FIELD* TI
*603666 SYNTAXIN 16; STX16
;;SYN16
*FIELD* TX

CLONING

SNAREs (SNAP receptors) are molecules involved in synaptic vesicle
read moredocking and fusion. V-SNAREs, found on vesicles, interact with t-SNAREs
(syntaxins), found on target membranes, in a specific manner. See
alpha-SNAP (603215). By searching sequence databases for syntaxin-like
proteins, Tang et al. (1998) identified a human cDNA encoding a novel
syntaxin, which they designated syntaxin-16 (SYN16). The predicted
307-amino acid protein contains the C-terminal hydrophobic tail anchor
characteristic of syntaxins, and several potential coiled-coil regions.
Using immunofluorescence, the authors determined that an epitope-tagged
SYN16 protein localized to the Golgi apparatus. Northern blot analysis
revealed that the 6.5-kb SYN16 mRNA is expressed ubiquitously.
Independently, Simonsen et al. (1998) isolated cDNAs encoding 3 isoforms
of syntaxin-16, syntaxin-16A, -16B, and -16C. The 16C isoform is
truncated, lacks the hydrophobic and coiled-coil regions, and localizes
to the cytoplasm. The authors found that the 16A isoform associates
posttranslationally with microsomes, and appears to be transported to
the Golgi via the endoplasmic reticulum.

MAPPING

The International Radiation Hybrid Mapping Consortium mapped the STX16
gene to chromosome 20 (TMAP STS-63081).

MOLECULAR GENETICS

In affected members and obligate carriers from 12 unrelated families
with pseudohypoparathyroidism Ib (603233), Bastepe et al. (2003)
identified a 3-kb heterozygous microdeletion located approximately 220
kb centromeric of exon 1A of the GNAS gene (139320), which was
postulated to disrupt imprinting. Four of 16 apparently sporadic
patients also had the deletion. In all examined cases, the deletion was
inherited from the mother, consistent with the observation of PHP Ib
developing only in offspring of female obligate carriers. The deletion
removed 3 of 8 exons encoding syntaxin-16 (603666.0001). Bastepe et al.
(2003) postulated that the microdeletion disrupts a putative cis-acting
element required for methylation at exon 1A and that this genetic defect
underlies the pathogenesis of PHP Ib.

Linglart et al. (2005) reported a novel heterozygous 4.4-kb
microdeletion in a large kindred with autosomal dominant PHP Ib.
Affected individuals from this kindred shared an epigenetic defect that
was indistinguishable from that observed in patients with the same
clinical disorder who carried the 3-kb microdeletion in the STX16 region
(Bastepe et al., 2003), i.e., an isolated loss of methylation at GNAS
exon A/B. The novel 4.4-kb microdeletion overlapped with a region of the
3-kb microdeletion and, similar to the latter deletion, removed several
exons of STX16. Because these microdeletions led to AD-PHP Ib only after
maternal transmission, Linglart et al. (2005) analyzed expression of
STX16 in lymphoblastoid cells of affected individuals with the 3-kb or
the 4.4-kb microdeletion, an individual with a NESP55 deletion, and a
healthy control. They found that STX16 mRNA was expressed in all cases
from both parental alleles. Thus, STX16 is apparently not imprinted, and
a loss-of-function mutation in 1 allele is unlikely to be responsible
for this disorder. Instead, the region of overlap between the 2
microdeletions likely harbors a cis-acting imprinting control element
that is necessary for establishing and/or maintaining methylation at
GNAS exon A/B, thus allowing normal expression of Gs-alpha expression in
the proximal renal tubules. In the presence of either of the 2
microdeletions, parathyroid hormone resistance appears to develop over
time, as documented in an affected individual who was diagnosed at birth
with a 4.4-kb deletion of STX16 but had normal serum parathyroid hormone
levels until the age of 21 months.

*FIELD* AV
.0001
PSEUDOHYPOPARATHYROIDISM, TYPE IB
STX16, 3-KB TO 4.4-KB MICRODELETION

In affected members and obligate carriers of 12 unrelated families with
pseudohypoparathyroidism type Ib (603233), Bastepe et al. (2003)
identified a 3-kb heterozygous microdeletion located approximately 220
kb centromeric of exon 1A, which they called exon A/B, of the GNAS gene
(see also 139320.0031). Four of 16 apparently sporadic patients also had
the deletion. Affected individuals with the microdeletion showed loss of
exon 1A methylation, but no other epigenetic abnormalities. In all
examined cases, the deletion was inherited from the mother, consistent
with the observation of PHP Ib developing only in offspring of female
obligate carriers. The deletion removed 3 of 8 exons encoding STX16, but
Bastepe et al. (2003) considered the involvement of STX16 in the
molecular pathogenesis of PHP Ib unlikely. They postulated that the
microdeletion disrupts a putative cis-acting control element required
for methylation at exon 1A and that this epigenetic defect underlies the
pathogenesis of PHP Ib.

Laspa et al. (2004) reported a Greek PHP Ib kindred with 4 affected
members and 3 obligate carriers who had the 3-kb deletion within STX16.
Symptomatic hypocalcemia was present only in the proband, but PTH was
elevated in all members who had inherited the 3-kb deletion maternally.
In all affected family members, urinary phosphate excretion was normal,
but 1,25-dihydroxyvitamin D levels were diminished. Affected individuals
displayed hypouricemia with increased fractional excretion of uric acid,
suggesting possible involvement of PTH in the renal handling of this
metabolite.

In all affected individuals and obligate carriers in a large kindred
with PHP Ib, Linglart et al. (2005) identified a 4.4-kb microdeletion
overlapping with a region of the 3-kb deletion identified by Bastepe et
al. (2003). The 4.4-kb deletion removed exons 2-4 of the STX16 gene,
whereas the 3-kb deletion removed exons 4-6. Both microdeletions lead to
PHP Ib only after maternal transmission, and affected individuals
exhibit loss of methylation only at GNAS exon A/B. Linglart et al.
(2005) determined that the STX16 gene is not imprinted, and proposed
that the region of overlap between the microdeletions contains a
cis-acting imprinting control element that is necessary for establishing
and/or maintaining methylation at GNAS exon A/B.

*FIELD* RF
1. Bastepe, M.; Frohlich, L. F.; Hendy, G. N.; Indridason, O. S.;
Josse, R. G.; Koshiyama, H.; Korkko, J.; Nakamoto, J. M.; Rosenbloom,
A. L.; Slyper, A. H.; Sugimoto, T.; Tsatsoulis, A.; Crawford, J. D.;
Juppner, H.: Autosomal dominant pseudohypoparathyroidism type Ib
is associated with a heterozygous microdeletion that likely disrupts
a putative imprinting control element of GNAS. J. Clin. Invest. 112:
1255-1263, 2003.

2. Laspa, E.; Bastepe, M.; Juppner, H.; Tsatsoulis, A.: Phenotypic
and molecular genetic aspects of pseudohypoparathyroidism type Ib
in a Greek kindred: evidence for enhanced uric acid excretion due
to parathyroid hormone resistance. J. Clin. Endocr. Metab. 89: 5942-5947,
2004.

3. Linglart, A.; Gensure, R. C.; Olney, R. C.; Juppner, H.; Bastepe,
M.: A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism
type Ib redefines the boundaries of a cis-acting imprinting control
element of GNAS. Am. J. Hum. Genet. 76: 804-814, 2005. Note: Erratum:
Am. J. Hum. Genet. 81: 196 only, 2007.

4. Simonsen, A.; Bremnes, B.; Ronning, E.; Aasland, R.; Stenmark,
H.: Syntaxin-16, a putative Golgi t-SNARE. Europ. J. Cell Biol. 75:
223-231, 1998.

5. Tang, B. L.; Low, D. Y. H.; Lee, S. S.; Tan, A. E. H.; Hong, W.
: Molecular cloning and localization of human syntaxin 16, a member
of the syntaxin family of SNARE proteins. Biochem. Biophys. Res.
Commun. 242: 673-679, 1998.

*FIELD* CN
John A. Phillips, III - updated: 11/17/2006
Victor A. McKusick - updated: 6/8/2005
Victor A. McKusick - updated: 3/8/2005

*FIELD* CD
Rebekah S. Rasooly: 3/23/1999

*FIELD* ED
ckniffin: 01/07/2009
carol: 6/29/2007
alopez: 11/17/2006
wwang: 6/27/2005
carol: 6/24/2005
terry: 6/8/2005
carol: 3/16/2005
terry: 3/8/2005
alopez: 3/23/1999

RBCC Red Blood Cell Collection

Full text data of STX16