Characterization of GUCA1A-associated dominant cone/cone-rod dystrophy: low prevalence among Japanese patients with inherited retinal dystrophies

Sci Rep. 2019 Nov 14;9(1):16851. doi: 10.1038/s41598-019-52660-1.

Abstract

GUCA1A gene variants are associated with autosomal dominant (AD) cone dystrophy (COD) and cone-rod dystrophy (CORD). GUCA1A-associated AD-COD/CORD has never been reported in the Japanese population. The purpose of this study was to investigate clinical and genetic features of GUCA1A-associated AD-COD/CORD from a large Japanese cohort. We identified 8 variants [c.C50_80del (p.E17VfsX22), c.T124A (p.F42I), c.C204G (p.D68E), c.C238A (p.L80I), c.T295A (p.Y99N), c.A296C (p.Y99S), c.C451T (p.L151F), and c.A551G (p.Q184R)] in 14 families from our whole exome sequencing database composed of 1385 patients with inherited retinal diseases (IRDs) from 1192 families. Three variants (p.Y99N, p.Y99S, and p.L151F), which are located on/around EF-hand domains 3 and 4, were confirmed as "pathogenic", whereas the other five variants, which did not co-segregate with IRDs, were considered "non-pathogenic". Ophthalmic findings of 9 patients from 3 families with the pathogenic variants showed central visual impairment from early to middle-age onset and progressive macular atrophy. Electroretinography revealed severely decreased or non-recordable cone responses, whereas rod responses were highly variable, ranging from nearly normal to non-recordable. Our results indicate that the three pathogenic variants, two of which were novel, underlie AD-COD/CORD with progressive retinal atrophy, and the prevalence (0.25%, 3/1192 families) of GUCA1A-associated IRDs may be low among Japanese patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Aged
  • Amino Acid Sequence
  • Cone Dystrophy / diagnosis
  • Cone Dystrophy / epidemiology
  • Cone Dystrophy / genetics*
  • Cone Dystrophy / pathology
  • Cone-Rod Dystrophies / diagnosis
  • Cone-Rod Dystrophies / epidemiology
  • Cone-Rod Dystrophies / genetics*
  • Cone-Rod Dystrophies / pathology
  • DNA Mutational Analysis
  • Electroretinography
  • Female
  • Fluorescein Angiography
  • Gene Expression
  • Genes, Dominant
  • Guanylate Cyclase-Activating Proteins / genetics*
  • Humans
  • Inheritance Patterns*
  • Japan / epidemiology
  • Male
  • Middle Aged
  • Pedigree
  • Polymorphism, Genetic*
  • Prevalence
  • Retina / metabolism
  • Retina / pathology
  • Sequence Alignment

Substances

  • GUCA1A protein, human
  • Guanylate Cyclase-Activating Proteins