Autosomal Recessive Achromatopsia Caused By A Homozygous Nonsense Mutation In A Novel ACHM Gene Involved In Cone Phototransduction

Abstract

Purpose: : Achromatopsia is an autosomal recessive retinal dystrophy characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Four genes, GNAT2, PDE6C, CNGA3 and CNGB3, have been implicated in ACHM, and all encode functional components of the cone phototransduction cascade.

Methods: : Following a functional candidate gene approach that focused on screening further genes involved in the phototransduction cascade we analyzed a cohort of over 650 index cases with ACHM or other cone disorders by PCR and Sanger sequencing. Analysis was complemented by haplotype reconstruction and immunohistochemical stainings of murine retinal sections.

Results: : We detected a homozygous single base change (c.35C>G) resulting in a nonsense mutation (p.Ser12*) in a novel ACHM gene. The c.35C>G mutation was present in three individuals from two independent families with a clinical diagnosis of incomplete ACHM. Patients from the two families share a common haplotype of 301 kb supporting that the c.35C>G (p.Ser12*) mutation is due to an ancestral mutational event. Moreover, we show by immunohistochemical co-localization studies in mouse retina that the encoded protein is expressed in all retinal cone photoreceptors.

Conclusions: : These findings add the novel ACHM gene to the growing set of genes involved in cone disorders, and demonstrate the important role of this protein in cone phototransduction.

Keywords: retinal degenerations: hereditary • genetics • color vision