Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy

J Clin Invest. 2018 Dec 3;128(12):5663-5675. doi: 10.1172/JCI96098. Epub 2018 Nov 12.

Abstract

Mutations in CNGA3 and CNGB3, the genes encoding the subunits of the tetrameric cone photoreceptor cyclic nucleotide-gated ion channel, cause achromatopsia, a congenital retinal disorder characterized by loss of cone function. However, a small number of patients carrying the CNGB3/c.1208G>A;p.R403Q mutation present with a variable retinal phenotype ranging from complete and incomplete achromatopsia to moderate cone dysfunction or progressive cone dystrophy. By exploring a large patient cohort and published cases, we identified 16 unrelated individuals who were homozygous or (compound-)heterozygous for the CNGB3/c.1208G>A;p.R403Q mutation. In-depth genetic and clinical analysis revealed a co-occurrence of a mutant CNGA3 allele in a high proportion of these patients (10 of 16), likely contributing to the disease phenotype. To verify these findings, we generated a Cngb3R403Q/R403Q mouse model, which was crossbred with Cnga3-deficient (Cnga3-/-) mice to obtain triallelic Cnga3+/- Cngb3R403Q/R403Q mutants. As in human subjects, there was a striking genotype-phenotype correlation, since the presence of 1 Cnga3-null allele exacerbated the cone dystrophy phenotype in Cngb3R403Q/R403Q mice. These findings strongly suggest a digenic and triallelic inheritance pattern in a subset of patients with achromatopsia/severe cone dystrophy linked to the CNGB3/p.R403Q mutation, with important implications for diagnosis, prognosis, and genetic counseling.

Keywords: Genetics; Molecular genetics; Ophthalmology; Retinopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Color Vision Defects* / genetics
  • Color Vision Defects* / metabolism
  • Color Vision Defects* / pathology
  • Cyclic Nucleotide-Gated Cation Channels* / genetics
  • Cyclic Nucleotide-Gated Cation Channels* / metabolism
  • Disease Models, Animal
  • HEK293 Cells
  • Heterozygote*
  • Humans
  • Ion Channel Gating*
  • Mice
  • Mice, Transgenic
  • Mutation
  • Mutation, Missense*
  • Retinal Cone Photoreceptor Cells* / metabolism
  • Retinal Cone Photoreceptor Cells* / pathology
  • Retinal Diseases* / genetics
  • Retinal Diseases* / metabolism
  • Retinal Diseases* / pathology

Substances

  • CNGA3 protein, human
  • Cnga3 protein, mouse
  • Cyclic Nucleotide-Gated Cation Channels