Mutations in the Cone Photoreceptor G-Protein a-Subunit Gene GNAT2 in Patients with Achromatopsia

Achromatopsia is an autosomal recessively inherited visual disorder that is present from birth and that features the absence of color discrimination. We here report the identification of five independent families with achromatopsia that segregate protein-truncation mutations in the GNAT2 gene, located on chromosome 1p13. GNAT2 encodes the cone photoreceptor–specific a-subunit of transducin, a G-protein of the phototransduction cascade, which couples to the visual pigment(s). Our results demonstrate that GNAT2 is the third gene implicated in achromatopsia. Achromatopsia, also referred to as “rod monochro-macy ” (ACHM2 [MIM 216900] and ACHM3 [MIM 262300]), is a congenital ocular disorder characterized by total color blindness, low visual acuity, photophobia, and nystagmus. It is inherited as an autosomal recessive trait, with an estimated prevalence of 1/30,000 (François 1961). Recently, we and others have shown that mutations in CNGA3 and CNGB3, which encode the a- and b-subunits of the cone photoreceptor cGMP-gated chan-nel, cause clinically indistinguishable forms of achroma-topsia, including Pingelapese blindness (Kohl et al. 1998, 2000; Sundin et al. 2000). However, screening for CNGA3 and CNGB3 muta-tions in a large cohort of patients with achromatopsia revealed further genetic heterogeneity in approximately one-third of the cases. The pursuit of additional genes involved in achromatopsia led us to consider GNAT2 as a prime candidate gene, because of its cone pho-toreceptor specificity and functional importance in the visual transduction process (Lerea et al. 1986; Blatt e