Homozygosity Mapping of the Achromatopsia Locus in the Pingelapese

Abstract

Achromatopsia, or total color blindness (also referred to as "rod monochromacy"), is a severe retinal disorder characterized clinically by an inability to distinguish colors, impaired visual acuity in daylight, photophobia, and nystagmus. Inherited as an autosomal recessive trait, achromatopsia is rare in the general population (1:20,000-1:50,000). Among the Pingelapese people of the Eastern Caroline Islands, however, the disorder occurs at an extremely high frequency, as recounted in Oliver Sacks's popular book The Island of the Colorblind: 4%-10% of this island population have the disorder and approximately 30% carry the gene. This extraordinary enrichment of the disease allele most likely resulted from a sharp reduction in population in the late 18th century, in the aftermath of a typhoon and subsequent geographic and cultural isolation. To obtain insights into the genetic basis of achromatopsia, as well as into the genetic history of this region of Micronesia, a genomewide search for linkage was performed in three Pingelapese kindreds with achromatopsia. A two-step search was used with a DNA pooling strategy, followed by genotyping of individual family members. Genetic markers that displayed a shift toward homozygosity in the affected DNA pool were used to genotype individual members of the kindreds, and an achromatopsia locus was identified on 8q21-q22. A maximal multipoint LOD score of 9.5 was observed with marker D8S1707. Homozygosity was seen for three adjacent markers (D8S275, D8S1119, and D8S1707), whereas recombination was observed with the flanking markers D8S1757 and D8S270, defining the outer boundaries of the disease-gene locus that spans a distance of <6.5cM.

Phototransduction in transgenic mice after targeted deletion of the rod transducin α-subunit

“…A genetic deletion of Tc␣ would be expected to result in achromatopsia or rod monochromacy. This condition is quite rare, and thus far, the few cases studied arose from mutations in the cone cGMP-gated channel (42) or in another protein of unknown function (43). If cones contain some Tr␣, then subtle cone abnormalities might be present in the absence of Tr␣, and partial cone function might be retained in the absence of Tc␣.…”

Gene Augmentation Therapy Restores Retinal Function and Visual Behavior in a Sheep Model of CNGA3 Achromatopsia

“…In most cases, it is caused by mutations in the cyclic nucleotide-gated (CNG) ion channel subunit A3 (α subunit) 3,4 or B3 (β subunit) of cone photoreceptors [5][6][7] . Studies performed mainly in North American and European populations have shown that mutations in the CNGB3 gene are the most common cause of ACHM, accounting for at least 50% of all cases 7,8 .…”

Homozygosity Mapping

“…In the second case, the emphasis is not only upon the finding of excess homozygosity, but excess homozygosity for a given marker allele, as it is assumed that only one disease gene is segregating within that family. Examples include the studies by Winick et al (1999) of achromatopsia in the Pingepalese (three large kindreds with 63 individuals), van Duijn et al (2001) of earlyonset Parkinsonism in a single family from a Dutch isolate (nine individuals genotyped, of which four were affected) and Hand et al (1999) of congenital endothelial dystrophy in one large inbred Irish kindred with 28 affected individuals.…”

“…This approach is applicable in samples of individuals from a single large kindred where it is reasonable to assume that the segregating disease gene is inherited from a single common ancestor. Examples include studies of achromatopsia (Winick et al, 1999), urofacial syndrome (Wang et al, 1997) and endothelial dystrophy (Hand et al, 1999). In summary, the technique consists of creating two DNA pools, one using DNA from affected individuals and the other using DNA from unaffected individuals.…”