GJA1 – Oculodentodigital Dysplasia (ODDD)

Oculodentodigital dysplasia (ODDD) is a pleiotropic developmental disorder caused by mutations in the gap junction protein Connexin 43, encoded by GJA1 ([HGNC:4274]). Clinically, ODDD manifests with characteristic craniofacial features (narrow nose, hypoplastic alae nasi), microphthalmia, microcornea, enamel hypoplasia and syndactyly. Although most cases follow autosomal dominant inheritance, rare autosomal recessive presentations have been described in consanguineous families ([PMID:15512999]).

Inheritance is primarily autosomal dominant, with numerous heterozygous missense variants exhibiting high penetrance and variable expressivity. Segregation of GJA1 mutations with the ODDD phenotype has been demonstrated across multiple multigenerational pedigrees, including a Brazilian kindred with eight affected individuals ([PMID:16219735]) and a recessive family with three affected siblings ([PMID:29902798]).

The variant spectrum exceeds 73 distinct mutations, predominantly missense substitutions clustering in extracellular and transmembrane domains, with recurrent alleles such as c.119C>T (p.Ala40Val) accounting for ~10% of cases ([PMID:32318302]). LoF variants—including frameshifts and nonsense changes—are less common but underline genetic heterogeneity and alternative inheritance modes when homozygous.

Functional studies in heterologous systems and patient‐derived cells reveal that ODDD‐associated Cx43 mutants fail to form conductive gap junction channels or hemichannels, and many exert dominant‐negative inhibition on wild-type Cx43 ([PMID:16531323]; [PMID:16418219]). Induced pluripotent stem cell models carrying p.Val216Leu display reduced Cx43 expression, impaired channel function and delayed osteogenic differentiation, linking molecular defects to tissue-specific phenotypes ([PMID:28177159]).

Mechanistically, disease arises from dominant‐negative and loss‐of‐function effects disrupting intercellular communication, with occasional hypomorphic alleles (e.g., p.Arg76His) causing Hallermann-Streiff/ODDD overlap in homozygosity ([PMID:14974090]).

Given the robust genetic and experimental concordance accumulated over >30 years, GJA1–ODDD meets criteria for a Definitive gene‐disease relationship. Key take-home: GJA1 sequencing informs diagnosis and familial counseling in ODDD, and functional assays guide pathogenicity of novel variants.

References

• Ophthalmic genetics • 2004 • Oculodentodigital dysplasia: study of ophthalmological and clinical manifestations in three boys with probably autosomal recessive inheritance. PMID:15512999
• American journal of medical genetics. Part A • 2005 • A novel mutation in the GJA1 gene in oculodentodigital dysplasia without syndactyly. PMID:16219735
• Cytogenetic and genome research • 2018 • Autosomal Recessive Oculodentodigital Dysplasia: A Case Report and Review of the Literature. PMID:29902798
• Case reports in ophthalmological medicine • 2020 • Oculodentodigital Dysplasia: A Case Report and Major Review of the Eye and Ocular Adnexa Features of 295 Reported Cases. PMID:32318302
• Cell communication & adhesion • 2005 • Functional characterization of oculodentodigital dysplasia-associated Cx43 mutants. PMID:16531323
• Journal of cell science • 2006 • Oculodentodigital dysplasia connexin43 mutations result in non-functional connexin hemichannels and gap junctions in C6 glioma cells. PMID:16418219
• Journal of bone and mineral research • 2017 • Connexin43 Mutant Patient-Derived Induced Pluripotent Stem Cells Exhibit Altered Differentiation Potential. PMID:28177159
• Human mutation • 2004 • A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype. PMID:14974090

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