Variant Phenotypes of Incomplete Achromatopsia in Two Cousins with GNAT2 Gene Mutations

Aarhus University, Aarhus, Central Jutland, Denmark
Investigative Ophthalmology &amp Visual Science (Impact Factor: 3.4). 12/2004; 45(12):4256-62. DOI: 10.1167/iovs.04-0317
Source: PubMed


The present study was designed to elucidate the molecular genetic basis of a congenital stationary cone dysfunction characterized by congenital nystagmus, moderate visual impairment, and markedly disparate color vision deficiencies between two affected cousins.
Ophthalmic examinations with emphasis on color vision and electrophysiology. Molecular genetic analysis of the X-linked cone opsin genes, mutation screening of the CNGA3, CNGB3, and GNAT2 genes, and heterologous splicing experiments.
Whereas the proband was found to carry a homozygous frameshift mutation (Tyr95fs) in GNAT2, her cousin was compound heterozygous for the Tyr95fs and a new intronic mutation c.461 + 24G-->A. Heterologous expression in COS7 cells showed that the latter causes a splicing defect that results in early translation termination. Yet, this mutation is leaky, giving rise to small amounts of correctly spliced transcripts and offer an explanation for the diverging clinical findings in the cousins, one best described as incomplete achromatopsia and the other with oligocone trichromacy.
The cases presented broaden the phenotypic spectrum of GNAT2 mutations and underline the increasing importance of molecular genetics in the clinical diagnosis of atypical ophthalmic phenotypes.

Download full-text


Available from: Thomas Rosenberg, Oct 08, 2015
39 Reads
  • Source
    • "The presentation of incomplete or atypical achromatopsia is similar, except that some color vision and improved acuity are present [7]. Most cases of human achromatopsia have been associated with mutations in three genes that play a major role in the cone phototransduction cascade. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lambs with congenital day blindness show diminished cone function, which is characteristic of achromatopsia, a congenital disorder described in humans and dogs. To identify gene(s) associated with sheep day blindness, we investigated mutations in the CNGA3, CNGB3, and GNAT2 genes which have been associated with achromatopsia. Sequencing the coding regions of those genes from four affected and eight non-affected lambs showed that all affected lambs were homozygous for a mutation in the CNGA3 gene that changes amino acid R236 to a stop codon. By PCR-RFLP-based testing, homozygosity for the stop codon mutation was detected in another 19 affected lambs. Non-affected individuals (n=386) were non-carriers or heterozygous for the mutation. While a selection program has been launched to eradicate the day blindness mutation from Improved Awassi flocks, a breeding nucleus of day-blind sheep has been established to serve as animal models for studying human achromatopsia.
    Genomics 10/2009; 95(2):101-4. DOI:10.1016/j.ygeno.2009.10.003 · 2.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, great advances have been made in our understanding of the molecular basis of colour vision defects, as well as of the patterns of genetic variation in individuals with normal colour vision. Molecular genetic analyses have explained the diversity of types and degrees of severity in colour vision anomalies, their frequencies, pronounced individual variations in test results, etc. New techniques have even enabled the determination of John Dalton's real colour vision defect, 150 years after his death. Inherited colour vision deficiencies most often result from the mutations of genes that encode cone opsins. Cone opsin genes are linked to chromosomes 7 (the S or "blue" gene) and X (the L or "red" gene and the M or "green" gene). The L and M genes are located on the q arm of the X chromosome in a head-to-tail array, composed of 2 to 6 (typically 3) genes--a single L is followed by one or more M genes. Only the first two genes of the array are expressed and contribute to the colour vision phenotype. The high degree of homology (96%) between the L and M genes predisposes them to unequal recombination, leading to gene deletion or the formation of hybrid genes (comprising portions of both the L and M genes), explaining the majority of the common red-green colour vision deficiencies. The severity of any deficiency is influenced by the difference in spectral sensitivity between the opsins encoded by the first two genes of the array. A rare defect, S monochromacy, is caused either by the deletion of the regulatory region of the array or by mutations that inactivate the L and M genes. Most recent research concerns the molecular basis of complete achromatopsia, a rare disorder that involves the complete loss of all cone function. This is not caused by mutations in opsin genes, but in other genes that encode cone-specific proteins, e.g. channel proteins and transducin.
    Srpski arhiv za celokupno lekarstvo 01/2005; 133(11-12):521-7. DOI:10.2298/SARH0512521C · 0.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in OPA1 are the most frequent cause underlying autosomal dominant optic atrophy (adOA). Until now only few putative splicing mutations in the OPA1 gene have been investigated at the mRNA level and all these result in exon skipping. Here, we report the identification and cDNA analysis of four intronic and three exonic OPA1 gene mutations that cause a variety of splicing defects including activation of cryptic splice sites in either flanking exon or intron sequences, and a leaky splicing mutation. Our results show that cDNA analysis is of prime importance for the full evaluation of the effect of putative splicing mutations in the OPA1 gene.
    Human Genetics 03/2006; 118(6):767-71. DOI:10.1007/s00439-005-0096-7 · 4.82 Impact Factor
Show more