Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the alpha subunit of cone transducin (GNAT2).
OBJECTIVE
To determine the molecular basis for achromatopsia using autozygosity mapping and positional candidate gene analysis.


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 alpha-transducin, the G protein that couples the cone pigments to cGMP-phosphodiesterase in phototransduction. Although cone alpha-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.
Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
I A
IA
Aligianis
T
T
Forshew
S
S
Johnson
M
M
Michaelides
C A
CA
Johnson
R C
RC
Trembath
D M
DM
Hunt
A T
AT
Moore
E R
ER
Maher
D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D003117:Color Vision Defects / Q000235:genetics* / Q000473:pathology; D003241:Consanguinity; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D015293:Transducin / Q000235:genetics*
D004247:DNA; D015293:Transducin