RBCC

Full text data of GNAI3

GNAI3 [Confidence: high (present in two of the MS resources)]
Guanine nucleotide-binding protein G(k) subunit alpha (G(i) alpha-3)

hRBCD IPI00220578
IPI00220578 guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 membrane n/a n/a n/a n/a n/a n/a n/a 2 2 n/a 2 2 4 n/a n/a 2 3 3 2 1 inner surface of plasma membrane n/a found at its expected molecular weight found at molecular weight

UniProt P08754
ID GNAI3_HUMAN Reviewed; 354 AA.
AC P08754; P17539;
DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 163.
DE RecName: Full=Guanine nucleotide-binding protein G(k) subunit alpha;
DE AltName: Full=G(i) alpha-3;
GN Name=GNAI3;
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].
RX PubMed=3109953; DOI=10.1016/0014-5793(87)81228-0;
RA Didsbury J.R., Snyderman R.;
RT "Molecular cloning of a new human G protein. Evidence for two Gi
RT alpha-like protein families.";
RL FEBS Lett. 219:259-263(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3120178; DOI=10.1073/pnas.84.22.7886;
RA Beals C.R., Wilson C.B., Perlmutter R.M.;
RT "A small multigene family encodes Gi signal-transduction proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:7886-7890(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2834384;
RA Itoh H., Toyama R., Kozasa T., Tsukamoto T., Matsuoka M., Kaziro Y.;
RT "Presence of three distinct molecular species of Gi protein alpha
RT subunit. Structure of rat cDNAs and human genomic DNAs.";
RL J. Biol. Chem. 263:6656-6664(1988).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2452165;
RA Codina J., Olate J., Abramowitz J., Mattera R., Cook R.G.,
RA Birnbaumer L.;
RT "Alpha i-3 cDNA encodes the alpha subunit of Gk, the stimulatory G
RT protein of receptor-regulated K+ channels.";
RL J. Biol. Chem. 263:6746-6750(1988).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3132707; DOI=10.1073/pnas.85.12.4153;
RA Kim S., Ang S.L., Bloch D.B., Bloch K.D., Kawahara Y., Tolman C.,
RA Lee R., Seidman J.G., Neer E.J.;
RT "Identification of cDNA encoding an additional alpha subunit of a
RT human GTP-binding protein: expression of three alpha i subtypes in
RT human tissues and cell lines.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:4153-4157(1988).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 21-354.
RX PubMed=2440724; DOI=10.1016/0014-5793(87)80900-6;
RA Suki W.N., Abramowitz J., Mattera R., Codina J., Birnbaumer L.;
RT "The human genome encodes at least three non-allelic G proteins with
RT alpha i-type subunits.";
RL FEBS Lett. 220:187-192(1987).
RN [10]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=17635935; DOI=10.1083/jcb.200604114;
RA Cho H., Kehrl J.H.;
RT "Localization of Gi alpha proteins in the centrosomes and at the
RT midbody: implication for their role in cell division.";
RL J. Cell Biol. 178:245-255(2007).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP VARIANT ARCND1 ARG-40.
RX PubMed=22560091; DOI=10.1016/j.ajhg.2012.04.002;
RA Rieder M.J., Green G.E., Park S.S., Stamper B.D., Gordon C.T.,
RA Johnson J.M., Cunniff C.M., Smith J.D., Emery S.B., Lyonnet S.,
RA Amiel J., Holder M., Heggie A.A., Bamshad M.J., Nickerson D.A.,
RA Cox T.C., Hing A.V., Horst J.A., Cunningham M.L.;
RT "A human homeotic transformation resulting from mutations in PLCB4 and
RT GNAI3 causes auriculocondylar syndrome.";
RL Am. J. Hum. Genet. 90:907-914(2012).
RN [13]
RP ERRATUM.
RA Rieder M.J., Green G.E., Park S.S., Stamper B.D., Gordon C.T.,
RA Johnson J.M., Cunniff C.M., Smith J.D., Emery S.B., Lyonnet S.,
RA Amiel J., Holder M., Heggie A.A., Bamshad M.J., Nickerson D.A.,
RA Cox T.C., Hing A.V., Horst J.A., Cunningham M.L.;
RL Am. J. Hum. Genet. 90:1116-1116(2012).
CC -!- FUNCTION: Guanine nucleotide-binding proteins (G proteins) are
CC involved as modulators or transducers in various transmembrane
CC signaling systems. G(k) is the stimulatory G protein of receptor-
CC regulated K(+) channels. The active GTP-bound form prevents the
CC association of RGS14 with centrosomes and is required for the
CC translocation of RGS14 from the cytoplasm to the plasma membrane.
CC May play a role in cell division.
CC -!- SUBUNIT: G proteins are composed of 3 units; alpha, beta and
CC gamma. The alpha chain contains the guanine nucleotide binding
CC site. Interacts with GPSM1. Interacts (via active GTP- or inactive
CC GDP-bound form) with RGS14 (By similarity).
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane. Cytoplasm,
CC cytoskeleton, microtubule organizing center, centrosome.
CC Note=Localizes in the centrosomes of interphase and mitotic cells.
CC Detected at the cleavage furrow and/or the midbody.
CC -!- DISEASE: Auriculocondylar syndrome 1 (ARCND1) [MIM:602483]: An
CC autosomal dominant craniofacial malformation syndrome
CC characterized by variable mandibular anomalies, including mild to
CC severe micrognathia, temporomandibular joint ankylosis, cleft
CC palate, and a characteristic ear malformation that consists of
CC separation of the lobule from the external ear, giving the
CC appearance of a question mark (question-mark ear). Other
CC frequently described features include prominent cheeks, cupped and
CC posteriorly rotated ears, preauricular tags, and microstomia.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the G-alpha family. G(i/o/t/z) subfamily.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M27543; AAA52579.1; -; mRNA.
DR EMBL; J03005; AAA52557.1; -; mRNA.
DR EMBL; M20604; AAA35895.1; -; Genomic_DNA.
DR EMBL; M20597; AAA35895.1; JOINED; Genomic_DNA.
DR EMBL; M20598; AAA35895.1; JOINED; Genomic_DNA.
DR EMBL; M20599; AAA35895.1; JOINED; Genomic_DNA.
DR EMBL; M20600; AAA35895.1; JOINED; Genomic_DNA.
DR EMBL; M20601; AAA35895.1; JOINED; Genomic_DNA.
DR EMBL; M20602; AAA35895.1; JOINED; Genomic_DNA.
DR EMBL; M20603; AAA35895.1; JOINED; Genomic_DNA.
DR EMBL; J03198; AAA35896.1; -; mRNA.
DR EMBL; J03238; AAA35939.1; -; mRNA.
DR EMBL; AF493907; AAM12621.1; -; mRNA.
DR EMBL; BT019974; AAV38777.1; -; mRNA.
DR EMBL; BC025285; AAH25285.1; -; mRNA.
DR PIR; S02348; RGHUI3.
DR RefSeq; NP_006487.1; NM_006496.3.
DR UniGene; Hs.73799; -.
DR UniGene; Hs.741171; -.
DR PDB; 2IHB; X-ray; 2.71 A; A=32-354.
DR PDB; 2ODE; X-ray; 1.90 A; A/C=4-350.
DR PDB; 2V4Z; X-ray; 2.80 A; A=4-350.
DR PDB; 4G5O; X-ray; 2.90 A; A/B/C/D=25-354.
DR PDB; 4G5R; X-ray; 3.48 A; A/B/C/D=25-354.
DR PDB; 4G5S; X-ray; 3.62 A; A/B/C/D=25-354.
DR PDBsum; 2IHB; -.
DR PDBsum; 2ODE; -.
DR PDBsum; 2V4Z; -.
DR PDBsum; 4G5O; -.
DR PDBsum; 4G5R; -.
DR PDBsum; 4G5S; -.
DR ProteinModelPortal; P08754; -.
DR SMR; P08754; 5-348.
DR IntAct; P08754; 21.
DR MINT; MINT-1146232; -.
DR STRING; 9606.ENSP00000358867; -.
DR BindingDB; P08754; -.
DR ChEMBL; CHEMBL4221; -.
DR PhosphoSite; P08754; -.
DR DMDM; 120996; -.
DR PaxDb; P08754; -.
DR PeptideAtlas; P08754; -.
DR PRIDE; P08754; -.
DR DNASU; 2773; -.
DR Ensembl; ENST00000369851; ENSP00000358867; ENSG00000065135.
DR GeneID; 2773; -.
DR KEGG; hsa:2773; -.
DR UCSC; uc001dxz.3; human.
DR CTD; 2773; -.
DR GeneCards; GC01P110091; -.
DR HGNC; HGNC:4387; GNAI3.
DR HPA; CAB022099; -.
DR MIM; 139370; gene.
DR MIM; 602483; phenotype.
DR neXtProt; NX_P08754; -.
DR Orphanet; 137888; Auriculo-condylar syndrome.
DR PharmGKB; PA173; -.
DR eggNOG; NOG322962; -.
DR HOGENOM; HOG000038730; -.
DR HOVERGEN; HBG063184; -.
DR InParanoid; P08754; -.
DR KO; K04630; -.
DR OMA; GEAARAX; -.
DR OrthoDB; EOG72C50B; -.
DR PhylomeDB; P08754; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_13685; Neuronal System.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; P08754; -.
DR ChiTaRS; GNAI3; human.
DR EvolutionaryTrace; P08754; -.
DR GeneWiki; GNAI3; -.
DR GenomeRNAi; 2773; -.
DR NextBio; 10906; -.
DR PRO; PR:P08754; -.
DR ArrayExpress; P08754; -.
DR Bgee; P08754; -.
DR CleanEx; HS_GNAI3; -.
DR Genevestigator; P08754; -.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0005834; C:heterotrimeric G-protein complex; IBA:RefGenome.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0030496; C:midbody; IDA:UniProtKB.
DR GO; GO:0042588; C:zymogen granule; IEA:Ensembl.
DR GO; GO:0031683; F:G-protein beta/gamma-subunit complex binding; IBA:RefGenome.
DR GO; GO:0031821; F:G-protein coupled serotonin receptor binding; IBA:RefGenome.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; IBA:RefGenome.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004871; F:signal transducer activity; IBA:RefGenome.
DR GO; GO:0007193; P:adenylate cyclase-inhibiting G-protein coupled receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0051301; P:cell division; IDA:UniProtKB.
DR GO; GO:0007194; P:negative regulation of adenylate cyclase activity; TAS:ProtInc.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0007268; P:synaptic transmission; TAS:Reactome.
DR GO; GO:0006810; P:transport; NAS:ProtInc.
DR GO; GO:0006906; P:vesicle fusion; IEA:Ensembl.
DR Gene3D; 1.10.400.10; -; 1.
DR InterPro; IPR001408; Gprotein_alpha_I.
DR InterPro; IPR001019; Gprotein_alpha_su.
DR InterPro; IPR011025; GproteinA_insert.
DR InterPro; IPR027417; P-loop_NTPase.
DR PANTHER; PTHR10218; PTHR10218; 1.
DR Pfam; PF00503; G-alpha; 1.
DR PRINTS; PR00318; GPROTEINA.
DR PRINTS; PR00441; GPROTEINAI.
DR SMART; SM00275; G_alpha; 1.
DR SUPFAM; SSF47895; SSF47895; 1.
DR SUPFAM; SSF52540; SSF52540; 2.
PE 1: Evidence at protein level;
KW 3D-structure; ADP-ribosylation; Cell cycle; Cell division;
KW Cell membrane; Complete proteome; Cytoplasm; Cytoskeleton;
KW Disease mutation; GTP-binding; Lipoprotein; Magnesium; Membrane;
KW Metal-binding; Myristate; Nucleotide-binding; Palmitate;
KW Reference proteome; Transducer.
FT INIT_MET 1 1 Removed (By similarity).
FT CHAIN 2 354 Guanine nucleotide-binding protein G(k)
FT subunit alpha.
FT /FTId=PRO_0000203692.
FT NP_BIND 40 47 GTP (By similarity).
FT NP_BIND 175 181 GTP (By similarity).
FT NP_BIND 200 204 GTP (By similarity).
FT NP_BIND 269 272 GTP (By similarity).
FT METAL 47 47 Magnesium (By similarity).
FT METAL 181 181 Magnesium (By similarity).
FT BINDING 326 326 GTP; via amide nitrogen (By similarity).
FT MOD_RES 178 178 ADP-ribosylarginine; by cholera toxin (By
FT similarity).
FT MOD_RES 351 351 ADP-ribosylcysteine; by pertussis toxin
FT (By similarity).
FT LIPID 2 2 N-myristoyl glycine (By similarity).
FT LIPID 3 3 S-palmitoyl cysteine (By similarity).
FT VARIANT 40 40 G -> R (in ARCND1).
FT /FTId=VAR_068558.
FT CONFLICT 21 21 R -> C (in Ref. 9; no nucleotide entry).
FT STRAND 34 39
FT HELIX 46 57
FT HELIX 63 68
FT HELIX 70 91
FT HELIX 100 110
FT TURN 111 116
FT HELIX 121 131
FT HELIX 134 141
FT HELIX 142 145
FT HELIX 152 157
FT HELIX 159 162
FT HELIX 171 175
FT STRAND 183 191
FT STRAND 194 201
FT HELIX 205 214
FT STRAND 219 226
FT HELIX 227 231
FT STRAND 237 241
FT HELIX 242 254
FT HELIX 257 259
FT STRAND 262 269
FT HELIX 271 278
FT HELIX 283 285
FT HELIX 296 308
FT TURN 314 316
FT STRAND 319 323
FT HELIX 329 346
SQ SEQUENCE 354 AA; 40532 MW; EAB6B4DD3646BC01 CRC64;
MGCTLSAEDK AAVERSKMID RNLREDGEKA AKEVKLLLLG AGESGKSTIV KQMKIIHEDG
YSEDECKQYK VVVYSNTIQS IIAIIRAMGR LKIDFGEAAR ADDARQLFVL AGSAEEGVMT
PELAGVIKRL WRDGGVQACF SRSREYQLND SASYYLNDLD RISQSNYIPT QQDVLRTRVK
TTGIVETHFT FKDLYFKMFD VGGQRSERKK WIHCFEGVTA IIFCVALSDY DLVLAEDEEM
NRMHESMKLF DSICNNKWFT ETSIILFLNK KDLFEEKIKR SPLTICYPEY TGSNTYEEAA
AYIQCQFEDL NRRKDTKEIY THFTCATDTK NVQFVFDAVT DVIIKNNLKE CGLY
//

MIM 139370
*RECORD*
*FIELD* NO
139370
*FIELD* TI
*139370 GUANINE NUCLEOTIDE-BINDING PROTEIN, ALPHA-INHIBITING ACTIVITY POLYPEPTIDE
3; GNAI3
read more;;G PROTEIN, ALPHA-INHIBITING 3
*FIELD* TX

CLONING

The GNAI3 gene encodes a 340-amino acid protein with a relative
molecular mass of approximately 40 kD. The protein sequence is closely
related to but distinct from that of GNAI2 (139360) (Itoh et al., 1988).

GENE STRUCTURE

Itoh et al. (1988) determined that the GNAI2 and GNAI3 genes contain 8
coding exons and possess identical exon-intron organization.

MAPPING

Using a cDNA probe against a mouse/human somatic cell hybrid panel,
Sparkes et al. (1987) mapped the alpha-inhibiting polypeptide-3 of G
protein to chromosome 1. See also Blatt et al. (1988). By in situ
hybridization, Wilkie et al. (1992) assigned the GNAI3 gene to
chromosome 1p13. They assigned the corresponding gene to mouse
chromosome 3 by study of restriction fragment length variation in an
interspecific backcross.

Baron et al. (1994) demonstrated that the Gnai3 gene in the hamster is
less than 60 kb from the Ampd2 gene (102771) with which it is
coamplified in coformycin-resistant cells. The hamster Gnai3 gene did
not contain sequences corresponding to the combined U6 snRNA and E
protein pseudogene, previously identified within intron 7 of the human
gene.

MOLECULAR GENETICS

In 2 unrelated probands with auriculocondylar syndrome (ARCND1; 602483),
Rieder et al. (2012) identified heterozygosity for a missense mutation
at a highly conserved residue in the GNAI3 gene (G40R; 139370.0001).
Functional analysis demonstrated significant reduction of downstream
targets of the G protein-coupled endothelin receptor pathway in mutant
cultured mandibular osteoblasts compared to controls.

Gordon et al. (2013) analyzed the GNAI3 and PLCB4 (600810) genes in 27
patients, including 8 with clinical ARCND, 5 with 'atypical' ARCND who
were previously described by McGowan et al. (2011), 3 with isolated
question mark ears (612798), 6 diagnosed with either
oculoauriculovertebral syndrome (OAVS) or Goldenhar syndrome (see
164210), and 4 with nonsyndromic auricular dysplasia with or without
mandibular dysplasia. In 1 ARCND proband and her affected father, they
identified a missense mutation in the GNAI3 gene (139370.0002). In
addition, 7 mutations were found in the PLCB4 gene in patients with
ARCND (ARCND2; 614669). Gordon et al. (2013) noted that of 15 reported
mutation-positive ARCND patients, 12 (80%) had a mutation in PLCB4 and 3
(20%) had a mutation in GNAI3.

*FIELD* AV
.0001
AURICULOCONDYLAR SYNDROME 1
GNAI3, GLY40ARG

In a mother and daughter with auriculocondylar syndrome (ARCND1;
602483), originally reported by Erlich et al. (2000), and in an
unrelated girl with ARCND, Rieder et al. (2012) identified
heterozygosity for a 118G-C transversion in exon 1 of the GNAI3 gene,
resulting in a gly40-to-arg (G40R) substitution at a highly conserved
residue. The sporadic patient inherited the mutation from her unaffected
father, indicating incomplete penetrance. The mutation was not found in
10,758 control chromosomes. The effects of the G40R substitution were
evaluated by assaying expression of known downstream targets in the G
protein-coupled endothelin receptor pathway, DLX5 (600028) and DLX6
(600030), in cultured mandibular osteoblasts: 6-fold and 8-fold
reductions in DLX5 and DLX6 expression, respectively, were demonstrated
in mutant samples compared to controls.

.0002
AURICULOCONDYLAR SYNDROME 1
GNAI3, SER47ARG

In a girl with auriculocondylar syndrome (ARCND1; 602483), Gordon et al.
(2013) identified heterozygosity for a c.141C-A transversion in the
GNAI3 gene, resulting in a ser47-to-arg (S47R) substitution at a highly
conserved residue within the G1 box. The mutation was inherited from her
mildly affected father, who had normal ears but large cheeks and
possible hypoplasia of the angle of the mandible.

*FIELD* RF
1. Baron, B.; Fernandez, M. A.; Toledo, F.; Le Roscouet, D.; Mayau,
V.; Martin, N.; Buttin, G.; Debatisse, M.: The highly conserved Chinese
hamster GNAI3 gene maps less than 60 kb from the AMPD2 gene and lacks
the intronic U6 snRNA present in its human counterpart. Genomics 24:
288-294, 1994.

2. Blatt, C.; Eversole-Cire, P.; Cohn, V. H.; Zollman, S.; Fournier,
R. E. K.; Mohandas, L. T.; Nesbitt, M.; Lugo, T.; Jones, D. T.; Reed,
R. R.; Weiner, L. P.; Sparkes, R. S.; Simon, M. I.: Chromosomal localization
of genes encoding guanine nucleotide-binding protein subunits in mouse
and human. Proc. Nat. Acad. Sci. 85: 7642-7646, 1988.

3. Erlich, M. S.; Cunningham, M. L.; Hudgins, L.: Transmission of
the dysgnathia complex from mother to daughter. Am. J. Med. Genet. 95:
269-274, 2000.

4. Gordon, C. T.; Vuillot, A.; Marlin, S.; Gerkes, E.; Henderson,
A.; AlKindy, A.; Holder-Espinasse, M.; Park, S. S.; Omarjee, A.; Sanchis-Borja,
M.; Ben Bdira, E.; Oufadem, M.; and 36 others: Heterogeneity of
mutational mechanisms and modes of inheritance in auriculocondylar
syndrome. J. Med. Genet. 50: 174-186, 2013.

5. Itoh, H.; Toyama, R.; Kozasa, T.; Tsukamoto, T.; Matsuoka, M.;
Kaziro, Y.: Presence of three distinct molecular species of G(i)
protein alpha subunit: structure of rat cDNAs and human genomic DNAs. J.
Biol. Chem. 263: 6656-6664, 1988.

6. McGowan, R.; Murday, V.; Kinning, E.; Garcia, S.; Koppel, D.; Whiteford,
M.: Novel features in auriculo-condylar syndrome. Clin. Dysmorph. 20:
1-10, 2011.

7. Rieder, M. J.; Green, G. E.; Park, S. S.; Stamper, B. D.; Gordon,
C. T.; Johnson, J. M.; Cunniff, C. M.; Smith, J. D.; Emery, S. B.;
Lyonnet, S.; Amiel, J.; Holder, M.; Heggie, A. A.; Bamshad, M. J.;
Nickerson, D. A.; Cox, T. C.; Hing, A. V.; Horst, J. A.; Cunningham,
M. L.: A human homeotic transformation resulting from mutations in
PLCB4 and GNAI3 causes auriculocondylar syndrome. Am. J. Hum. Genet. 90:
907-914, 2012. Note: Erratum: Am. J. Hum. Genet. 90: 1116 only, 2012.
Erratum: Am. J. Hum. Genet. 91: 397 only, 2012.

8. Sparkes, R. S.; Cohn, V. H.; Mohandas, T.; Zollman, S.; Cire-Eversole,
P.; Amatruda, T. T.; Reed, R. R.; Lochrie, M. A.; Simon, M. I.: Mapping
of genes encoding the subunits of guanine nucleotide-binding protein
(G-proteins) in humans. (Abstract) Cytogenet. Cell Genet. 46: 696
only, 1987.

9. Wilkie, T. M.; Gilbert, D. J.; Olsen, A. S.; Chen, X.-N.; Amatruda,
T. T.; Korenberg, J. R.; Trask, B. J.; de Jong, P.; Reed, R. R.; Simon,
M. I.; Jenkins, N. A.; Copeland, N. G.: Evolution of the mammalian
G protein alpha subunit multigene family. Nature Genet. 1: 85-91,
1992.

*FIELD* CN
Marla J. F. O'Neill - updated: 09/13/2013
Marla J. F. O'Neill - updated: 6/4/2012

*FIELD* CD
Victor A. McKusick: 9/22/1987

*FIELD* ED
carol: 09/13/2013
carol: 9/11/2012
carol: 6/22/2012
terry: 6/4/2012
carol: 6/4/2012
carol: 7/2/1998
carol: 1/9/1995
carol: 5/19/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
root: 11/10/1988

MIM 602483
*RECORD*
*FIELD* NO
602483
*FIELD* TI
#602483 AURICULOCONDYLAR SYNDROME 1; ARCND1
;;QUESTION MARK EARS SYNDROME
*FIELD* TX
read moreA number sign (#) is used with this entry because of evidence that
auriculocondylar syndrome-1 (ARCND1) is caused by heterozygous mutation
in the GNAI3 gene (139370) on chromosome 1p13.

DESCRIPTION

Auriculocondylar syndrome (ARCND) is an autosomal dominant disorder of
the first and second pharyngeal arches and is characterized by malformed
ears (question mark ears), prominent cheeks, microstomia, abnormal
temporomandibular joint, and mandibular condyle hypoplasia (summary by
Masotti et al., 2008).

- Genetic Heterogeneity of Auriculocondylar Syndrome

Auriculocondylar syndrome-2 (ARCND2; 614669) is caused by mutation in
the PLCB4 gene (600810) on chromosome 20p12.3-p12.2.

See also 612798 for isolated question mark ears.

CLINICAL FEATURES

Uuspaa (1978) reported a mother and 2 sons with bilateral external ear
malformations and hypoplastic mandible.

Jampol et al. (1998) described a family in which several individuals in
at least 5 generations had prominent, malformed ears, abnormality of the
temporomandibular joint and condyle of the mandible, and microstomia,
but normal hearing and normal ossicles of the middle ear. The ear
deformity was referred to as 'prominent, constricted ears.' This may be
the same as that called 'question mark ear,' by Brodovsky and Westreich
(1997). The question mark ear had been noted in 2 sibs with unaffected
parents by Takato et al. (1989). In the kindred reported by Jampol et
al. (1998), the ear deformity was present in the father of the
propositus and in a paternal aunt and her daughter, a paternal uncle,
the paternal grandmother, and the paternal grandmother's father, as well
as the paternal grandmother's paternal grandmother. None of these
affected relatives was known to have had other birth defects. When the
propositus was examined at the age of 8 years, the prominent ears were
described as narrowing at the junction of the lower third and upper
two-thirds and had no antihelix. The mandible was prognathic with type
III malocclusion. This anomaly is presumably inherited as an autosomal
dominant.

Guion-Almeida et al. (1999) reported a patient with strikingly malformed
ears, abnormalities of the condyle of the mandible, micrognathia, small
mouth, and cleft uvula. The parents were nonconsanguineous, with normal
phenotype and normal radiologic findings of the mandible and
temporomandibular joint. The authors concluded that this patient may be
affected with the condition reported by Jampol et al. (1998). They
suggested that the absence of findings in the parents supports the
possibility of a new mutation in this case.

Guion-Almeida et al. (2002) described several members with
auriculocondylar syndrome in 3 generations of a family. At 5 months of
age the proband had microstomia with severely limited opening of her
mouth, marked micrognathia, glossoptosis, and low-set ears with atretic
external auditory canals and constriction at the junction of the upper
two-thirds and lower third of the pinna. A CT scan excluded
abnormalities of the bones of the middle ear. X-ray films showed
condylar agenesis. The proband's father had similar facial features and
ears but also had a history of cleft palate and sensorineural hearing
loss. Guion-Almeida et al. (2002) also described a 9-year-old boy with
auriculocondylar syndrome whose parents were consanguineous. He had
characteristic ears, unique bilateral appendages emerging from the
anterior tonsillar pillars almost into the tip of the normal uvula, and
a hypoplastic mandibular condyle on x-ray films. He also had mild ptosis
and mild developmental delay, which the authors noted was also present
in the patient described by Priolo et al. (2000).

Guion-Almeida et al. (2002) compared the findings in reported patients
with auriculocondylar syndrome with those in the mother and daughter
reported by Erlich et al. (2000) as having the dysgnathia complex
(202650). They concluded that the patients of Erlich et al. (2000)
actually had auriculocondylar syndrome.

In a literature review of 14 patients, Storm et al. (2005) reported the
most common clinical signs of ARCND: abnormalities of the TMJ/condyle
(100%), ear constriction (96.8%), micrognathia (71%), abnormal palate
(62.5%), prominent cheeks (57.1%), microstomia (51.9%), glossoptosis
(45.5%), respiratory distress (36.4%), stenotic ear canals (30%), and
hearing loss (21%). Some patients may need orthodontic treatment, speech
therapy, or orthognathic surgery. Storm et al. (2005) noted that the
phenotype is highly variable, even within families.

Nezarati and Aftimos (2007) reported a 26-year-old man, born of
first-cousin parents, with severe micrognathia, absence of the upper
portion of the helices, atresia of the external meati and absence of the
middle ear ossicles, mildly downslanting palpebral fissures, and a
highly arched palate with a submucous cleft. The authors suggested that
this constellation of findings might represent a more severe
manifestation of the auriculocondylar syndrome or a previously
undescribed syndrome.

McGowan et al. (2011) reported 9 ARCND patients from 6 families.
Micrognathia, microstomia, and prominent cheeks were present in all of
the patients, but there was a significant degree of phenotypic
variability. Six patients, who all had the typical auricular deformities
of ARCND, underwent imaging, and all had either mandibular hypoplasia or
abnormalities of the mandibular condyle. Facial asymmetry was a common
feature, occurring in 7 of the 9 patients. In addition, patients in this
series had other clinical signs not previously reported in ARCND,
including facial cleft and preauricular and cheek pits. Citing the delay
in diagnosis of ARCND as well as the phenotypic spectrum of
abnormalities observed in their series, McGowan et al. (2011) suggested
that ARCND is largely unrecognized and might be more common than would
appear from published reports.

Gordon et al. (2013) studied a father and daughter with ARCND. The
daughter displayed asymmetric micrognathia, malocclusion, microstomia,
and a notch between the lobe and helix of the right ear. She also
displayed mildly hypoplastic first ribs on x-ray. Her father had normal
ears but large cheeks and possible hypoplasia of the angle of the
mandible. Mandibular x-rays were not available for the father.

PATHOGENESIS

Rieder et al. (2012) studied 8 probands with auriculocondylar syndrome
and available affected relatives. In each case, mandibular ankylosis was
progressive, of variable severity, and characterized by inconsistent
fusion to the medial and lateral pterygoid plates. All cases
demonstrated a similar phenotype, consisting of a lateral mandibular
bony prominence with or without temporomandibular joint ankylosis, and
had features consistent with classic ARCND. The anatomic features of
these cases led Rieder et al. (2012) to hypothesize that the
malformations observed in patients with ARCND are due to a homeotic
transformation, with the mandible assuming a maxillary phenotype.

MAPPING

After excluding 3 known loci associated with disorders of first and
second branchial arches through segregation analysis, Masotti et al.
(2008) conducted genomewide linkage analysis in 2 large families with
auriculocondylar syndrome, 1 of which (family 'F2') was previously
reported by Guion-Almeida et al. (2002). Masotti et al. (2008) obtained
a maximum lod score of 3.01 on chromosome 1p21.1-q23.3 (at theta = 0.0)
in family F2; haplotype reconstruction defined a 43-cM (60-Mb) critical
region between D1S206 and D1S2878, which the authors stated contained at
least 250 genes. This locus was not linked to the phenotype segregating
in the other family, however, suggesting genetic heterogeneity for the
disorder.

MOLECULAR GENETICS

By whole-exome sequencing followed by filtering of exome data, Rieder et
al. (2012) identified a heterozygous missense mutation in the GNAI3 gene
(139370.0001) on chromosome 1p13.3 in a mother and daughter with
auriculocondylar syndrome, who were originally reported by Erlich et al.
(2000), and in another unrelated ARCND proband. The unrelated proband
inherited the mutation from her unaffected father, demonstrating
incomplete penetrance. The mutation was not found in 10,758 control
chromosomes.

Gordon et al. (2013) analyzed the GNAI3 and PLCB4 genes in 27 patients,
including 8 with clinical ARCND, 5 with 'atypical' ARCND who were
previously described by McGowan et al. (2011), 3 with isolated question
mark ears (612798), 6 diagnosed with either oculoauriculovertebral
syndrome (OAVS) or Goldenhar syndrome (see 164210), and 4 with
nonsyndromic auricular dysplasia with or without mandibular dysplasia.
In a female proband with ARCND and her affected father, a missense
mutation was identified in the GNAI3 gene (S47R; 139370.0002). In
addition, 7 mutations were found in the PLCB4 gene. Gordon et al. (2013)
noted that of 15 reported mutation-positive ARCND patients, 12 (80%) had
a mutation in PLCB4 and 3 (20%) had a mutation in GNAI3. Among the
mutation-negative patients were the 5 probands with 'atypical' ARCND
originally reported by McGowan et al. (2011) (cases 1, 3, 4a, 5, and
6a). Gordon et al. (2013) stated that none of these 5 probands exhibited
the indentation or cleft between the helix and lobe that is
characteristic of PLCB4/GNAI3 mutation-positive ARCND cases. They
concluded that despite intrafamilial variation in severity, the
PLCB4/GNAI3-related auricular phenotype is highly specific and
distinguishable from other human ear dysplasias.

*FIELD* RF
1. Brodovsky, S.; Westreich, M.: Question mark ear: a method for
repair. Plast. Reconstr. Surg. 100: 1254-1257, 1997.

2. Erlich, M. S.; Cunningham, M. L.; Hudgins, L.: Transmission of
the dysgnathia complex from mother to daughter. Am. J. Med. Genet. 95:
269-274, 2000.

3. Gordon, C. T.; Vuillot, A.; Marlin, S.; Gerkes, E.; Henderson,
A.; AlKindy, A.; Holder-Espinasse, M.; Park, S. S.; Omarjee, A.; Sanchis-Borja,
M.; Ben Bdira, E.; Oufadem, M.; and 36 others: Heterogeneity of
mutational mechanisms and modes of inheritance in auriculocondylar
syndrome. J. Med. Genet. 50: 174-186, 2013.

4. Guion-Almeida, M. L.; Kokitsu-Nakata, N. M.; Zechi-Ceide, R. M.;
Vendramini, S.: Auriculo-condylar syndrome: further evidence for
a new disorder. Am. J. Med. Genet. 86: 130-133, 1999.

5. Guion-Almeida, M. L.; Zechi-Ceide, R. M.; Vendramini, S.; Kokitsu-Nakata,
N. M.: Auriculo-condylar syndrome: additional patients. Am. J. Med.
Genet. 112: 209-214, 2002.

6. Jampol, M.; Repetto, G.; Keith, D. A.; Curtin, H.; Remensnyder,
J.; Holmes, L. B.: Prominent, constricted ears with malformed condyle
of the mandible. Am. J. Med. Genet. 75: 449-452, 1998.

7. Masotti, C.; Oliveira, K. G.; Poerner, F.; Splendore, A.; Souza,
J.; da Silva Freitas, R.; Zechi-Ceide, R.; Guion-Almeida, M. L.; Passos-Bueno,
M. R.: Auriculo-condylar syndrome: mapping of a first locus and evidence
for genetic heterogeneity. Europ. J. Hum. Genet. 16: 145-152, 2008.

8. McGowan, R.; Murday, V.; Kinning, E.; Garcia, S.; Koppel, D.; Whiteford,
M.: Novel features in auriculo-condylar syndrome. Clin. Dysmorph. 20:
1-10, 2011.

9. Nezarati, M. M.; Aftimos, S.: Microtia, severe micrognathia and
absent ossicles: auriculo-condylar syndrome or new entity? Clin.
Dysmorph. 16: 9-13, 2007.

10. Priolo, M.; Lerone, M.; Rosaia, L.; Calcagno, E. P.; Sadeghi,
A. K.; Ghezzi, F.; Ravazzollo, R.; Silengo, M.: Question mark ears,
temporo-mandibular joint malformation and hypotonia: auriculo-condylar
syndrome or a distinct entity? Clin. Dysmorph. 9: 277-280, 2000.

11. Rieder, M. J.; Green, G. E.; Park, S. S.; Stamper, B. D.; Gordon,
C. T.; Johnson, J. M.; Cunniff, C. M.; Smith, J. D.; Emery, S. B.;
Lyonnet, S.; Amiel, J.; Holder, M.; Heggie, A. A.; Bamshad, M. J.;
Nickerson, D. A.; Cox, T. C.; Hing, A. V.; Horst, J. A.; Cunningham,
M. L.: A human homeotic transformation resulting from mutations in
PLCB4 and GNAI3 causes auriculocondylar syndrome. Am. J. Hum. Genet. 90:
907-914, 2012. Note: Erratum: Am. J. Hum. Genet. 90: 1116 only, 2012.
Erratum: Am. J. Hum. Genet. 91: 397 only, 2012.

12. Storm, A. L.; Johnson, J. M.; Lammer, E.; Green, G. E.; Cunniff,
C.: Auriculo-condylar syndrome is associated with highly variable
ear and mandibular defects in multiple kindreds. Am. J. Med. Genet. 138A:
141-145, 2005.

13. Takato, T.; Takeda, H.; Kamei, M.; Uchiyama, K.: The question
mark ear (congenital auricular cleft): a familial case. Ann. Plast.
Surg. 22: 69-73, 1989.

14. Uuspaa, V.: Combined bilateral external ear deformity and hypoplastic
mandible: case report. Scand. J. Plast. Reconstr. Surg. 12: 165-167,
1978.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Head];
Macrocephaly (25%);
[Face];
Micrognathia;
Round facial appearance;
Prominent cheeks;
[Ears];
Malformed ears;
Auricular clefts;
Cleft at the junction of the lobule and helix;
Lobule may be separately from the rest of the external ear;
Cleft at the superior portion of the pinna;
Cupped pinna;
Overfolding of the superior helices;
Underdeveloped superior helices;
Pre- and post-auricular skin or cartilaginous tags;
Low-set ears;
Posteriorly rotated ears;
Stenotic ear canals (30%);
Ear constriction (97%);
[Mouth];
Microstomia (52%);
Glossoptosis (46%);
Abnormal palate (63%);
Cleft palate;
Mastication difficulties;
Speech articulation difficulties;
[Teeth];
Crowded teeth;
Malocclusion;
Open anterior bite;
Posterior crossbite

RESPIRATORY:
Respiratory difficulties due to orofacial malformations (36%);
Apnea;
Snoring

SKELETAL:
[Skull];
Mandibular condyle hypoplasia;
Mandibular condyle aplasia;
Mandibular agenesis;
Asymmetric mandible;
Short mandibular rami;
Small mandibular coronoid processes;
Temporomandibular joint abnormalities;
Ankylosis of the temporomandibular joints

MISCELLANEOUS:
Congenital disorder;
Variable phenotype within families

*FIELD* CD
Cassandra L. Kniffin: 10/21/2005

*FIELD* ED
ckniffin: 10/21/2005

*FIELD* CN
Marla J. F. O'Neill - updated: 09/13/2013
Marla J. F. O'Neill - updated: 6/4/2012
Marla J. F. O'Neill - updated: 3/5/2010
Marla J. F. O'Neill - updated: 5/21/2009
Marla J. F. O'Neill - updated: 4/8/2009
Cassandra L. Kniffin - updated: 10/21/2005
Deborah L. Stone - updated: 4/22/2003
Sonja A. Rasmussen - updated: 10/5/1999

*FIELD* CD
Victor A. McKusick: 3/30/1998

*FIELD* ED
carol: 09/13/2013
carol: 9/11/2012
carol: 6/22/2012
carol: 6/4/2012
wwang: 3/9/2010
terry: 3/5/2010
wwang: 5/22/2009
terry: 5/21/2009
wwang: 4/16/2009
terry: 4/8/2009
alopez: 4/12/2006
wwang: 11/8/2005
ckniffin: 10/21/2005
tkritzer: 11/3/2003
carol: 4/22/2003
carol: 10/5/1999
dholmes: 4/17/1998
carol: 3/30/1998

RBCC Red Blood Cell Collection

Full text data of GNAI3