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.
Aligianis
I A
IA
Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Forshew
T
T
Johnson
S
S
Michaelides
M
M
Johnson
C A
CA
Trembath
R C
RC
Hunt
D M
DM
Moore
A T
AT
Maher
E R
ER
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