ARHGAP35 is a novel factor disrupted in human developmental eye phenotypes.

Area of Science:

• Genetics
• Developmental Biology
• Ophthalmology

Background:

• The ARHGAP35 gene is involved in crucial cellular processes like migration, division, and morphogenesis.
• Previous research suggests ARHGAP35 plays a role in cancer and embryonic development in mice, affecting eyes, neural tissue, and renal structures.

Purpose of the Study:

• To investigate the role of ARHGAP35 in human congenital eye malformations.
• To identify genetic variants in ARHGAP35 associated with anophthalmia, microphthalmia, coloboma, and anterior segment dysgenesis.

Main Methods:

• Genetic analysis of individuals from four families affected with congenital eye disorders.
• Variant calling and pathogenicity prediction for identified ARHGAP35 mutations.
• Correlation of genotype with phenotypic presentation, including ocular and non-ocular anomalies.

Main Results:

• Identification of pathogenic ARHGAP35 variants in five individuals across four families with developmental eye disorders.
• Observed variable non-ocular phenotypes, including renal, neurological, and cardiac anomalies, in some affected individuals.
• Three variants were located at the C-terminus, with two causing frameshifts and one a missense change in the Rho-GAP domain; a fourth nonsense variant was also identified.

Conclusions:

• This study implicates ARHGAP35 as a novel gene associated with human developmental eye phenotypes.
• The clustering of variants at the C-terminus suggests a potential common pathogenic mechanism for ocular disease.
• Further research is warranted to fully elucidate the role of ARHGAP35 in ocular development and disease.