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  • Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the α subunit of cone transducin (GNAT2)

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Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the α subunit of cone transducin (GNAT2)
  1. I A Aligianis1,2,
  2. T Forshew1,
  3. S Johnson1,
  4. M Michaelides3,
  5. C A Johnson3,
  6. R C Trembath4,
  7. D M Hunt3,
  8. A T Moore3,
  9. E R Maher1,2
  1. 1Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
  2. 2West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham B15 2TG, UK
  3. 3Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EV, UK
  4. 4Division of Medical Genetics, Departments of Medicine and Genetics, University of Leicester, Leicester LE1 7RH, UK
  1. Correspondence to:
 Professor E R Maher, Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, The Medical School, Birmingham B15 2TT, UK;
 ermaher{at}hgmp.mrc.ac.uk

Abstract

Objective: To determine the molecular basis for achromatopsia using autozygosity mapping and positional candidate gene analysis.

Design and methods: A large consanguineous Pakistani family containing six subjects with autosomal recessive complete achromatopsia was ascertained. After excluding linkage to the two known achromatopsia genes (CNGA3 and CNGB3), a genome wide linkage screen was undertaken.

Results: Significant linkage was detected to a 12 cM autozygous segment between markers D1S485 and D1S2881 on chromosome 1p13. Direct sequence analysis of the candidate gene GNAT2 located within this interval identified a frameshift mutation in exon 7 (c842_843insTCAG; M280fsX291) that segregated with the disease.

Conclusions: The GNAT2 gene codes for cone α-transducin, the G protein that couples the cone pigments to cGMP-phosphodiesterase in phototransduction. Although cone α-transducin has a fundamental role in cone phototransduction, mutations in GNAT2 have not been described previously. Since mutations in the CNGA3 gene may cause a variety of retinal dystrophies (complete and incomplete achromatopsia and progressive cone dystrophy), GNAT2 mutations may also prove to be implicated in other forms of retinal dystrophy with cone dysfunction.

  • achromatopsia
  • α-transducin
  • GNAT2
  • autozygosity mapping

https://doi.org/10.1136/jmg.39.9.656

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