GIPC3 – Autosomal Recessive Nonsyndromic Hearing Loss 15

GIPC3 encodes a PDZ domain–containing protein crucial for inner ear hair cell function. Pathogenic variants in GIPC3 underlie autosomal recessive nonsyndromic hearing loss type 15 (ARNSHL15) (MONDO:0011160). The inheritance is autosomal recessive, with affected individuals harboring bi-allelic disruptive alleles. Clinical presentation ranges from prelingual severe-to-profound sensorineural hearing impairment to age-dependent progressive loss.

Genetic studies identified seven distinct GIPC3 alleles—one frameshift and six missense—in six large unrelated families, supporting autosomal recessive inheritance and cosegregation with DFNB72 hearing loss (c.565C>T (p.Arg189Cys)) PMID:21660509. No GIPC3 mutations were detected in a distinct DFNB81-linked family, refining locus boundaries and confirming genetic heterogeneity (PMID:21660509). Variants include missense changes altering conserved residues (e.g., p.Arg189Cys) and frameshift alleles predicted to truncate the PDZ domain.

Segregation analysis across six pedigrees provides statistically significant linkage (LOD >3) to chromosome 19p13.3–q13.31 and confirms co-segregation of GIPC3 variants with hearing impairment PMID:21660509. Affected relatives carrying homozygous or compound heterozygous alleles exhibit early-onset sensorineural loss, consistent with recessive transmission. No evidence for dominant-negative effects has been reported.

Functional assays demonstrated that the canonical splice acceptor mutation c.226-1G>T causes aberrant splicing of exon 2, resulting in a frameshift and premature termination codon in minigene experiments PMID:25296581. These data support a loss-of-function mechanism via nonsense-mediated decay. Concordant findings in Gipc3-deficient mice recapitulate progressive high-frequency hearing loss.

Collectively, genetic linkage, segregation in six families, and functional concordance of splice-site and coding variants establish a Strong clinical validity for GIPC3–ARNSHL15 association. Screening for GIPC3 variants is recommended for early diagnosis and management of nonsyndromic sensorineural hearing loss (PMID:36704659).

Key Take-home: Bi-allelic loss-of-function and missense mutations in GIPC3 cause autosomal recessive nonsyndromic hearing loss, justifying inclusion in diagnostic gene panels.

References

• Human genetics • 2011 • Mutations of GIPC3 cause nonsyndromic hearing loss DFNB72 but not DFNB81 that also maps to chromosome 19p. PMID:21660509
• Journal of human genetics • 2014 • A canonical splice site mutation in GIPC3 causes sensorineural hearing loss in a large Pakistani family. PMID:25296581
• Frontiers in synaptic neuroscience • 2022 • A review of the mechanisms underlying the role of the GIPC3 gene in hereditary deafness. PMID:36704659

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