A locus for a human hereditary cataract is closely linked to the gamma-crystallin gene family.

Abstract

Within the human y-crystallin gene cluster polymorphic Taq I sites are present. These give rise to three sets of allelic fragments from the -crystallin genes. Together these restriction fragment length polymorphisms define eight possi. ble haplotypes, three of which (Q, R, and S) were found in the Dutch and English population. A fourth haplotype (P) was detected within a family in which a hereditary Coppock-like cataract of the embryonic lens nucleus occurs in heterozygotes, Haplotype P was found only in family members who suffered from cataract, and all family members who suffered from cataract had haplotype P. The absolute correlation between the presence of haplotype P and cataract within this family shows that the y-crystallin gene cluster and the locus for the Coppocklike cataract are closely linked [logarithm of odds (lod) score of 7.58 at its maximum at 0 = 0]. This linkage provides genetic evidence that the primary cause of a cataract in humans could possibly be a lesion in a crystallin gene.Opacity of the lens, cataract, is the most common lens abnormality in humans. Often it is but one of the symptoms of a complex disease syndrome, and its primary cause must then be sought in the environment of the lens and not in the lens itself (1). When its occurrence is not associated with any other physical anomalies, as in some forms of hereditary cataract (for review, see ref.2), it could be due to an inherent lens defect such as a dysfunction of the genes coding for lens-specific proteins. For example, the abundant watersoluble structural lens proteins, the a-, P-, and y-crystallins, are thought to be involved in establishing the transparency of the lens and a mutation in one of these proteins might be expected to cause cataract. Unfortunately, the changes in physical properties of the lens proteins that occur during cataractogenesis are too complex to allow one to discern mutant proteins (3), and studies of cataractous lenses have therefore failed to provide direct evidence for the involvement of aberrant crystallins (or other lens-specific proteins). A direct contribution of crystallins to cataractogenesis has only been shown for coldcataract, which is due to a phase transition in the protein-water mixture in the lens (4).A difference in the population of crystallin transcripts has been noted in two murine hereditary cataracts: the lens ofthe Philly mouse lacks a P-crystallin mRNA (5), while a premature cessation of y-crystallin mRNA synthesis was seen in the lens of the CatFr mouse (6). The interpretation ofthese results in terms of the molecular lesion in these cataracts is not straightforward, however, since both cataracts are thought to be osmotic ones (2, 6). The results of the studies of these (and other) MATERIALS AND METHODSIsolation, Restriction, and Hybridization of Genomic DNA. DNA was isolated from whole blood essentially as described by Bell et al. (9). Aliquots (10 gg) were digested with Taq I under the conditions recommended by the suppliers of the enzyme (Boehringer Mannheim), and ...

Gamma-crystallins of the human eye lens: expression analysis of five members of the gene family.

“…The impetus for our present study was provided by the recent finding that a dominantly inherited cataract is closely linked to the human y-crystallin gene family (20) and that, in contrast to the y-crystallins of a number of species (8,31,40), the corresponding proteins in humans have been considerably less well characterized. This is primarily due to the fact that the human ly-crystallins undergo extensive posttranslational modification during aging, leading to significant protein microheterogeneity that complicates their separation and physical characterization (32,33; P. Russell, D. Garland, J. S. Zigler, Jr., S. 0.…”

“…The importance of developing such knowledge is underscored by the recent finding that a dominantly inherited cataract is closely linked to the locus encoding the human y-crystallins (20), which has been localized to chromosome 2, region q33-36 (5,34,39). While only two distinct human y-crystallin protein species have been described (41,42), studies at the molecular level have provided evidence for at least seven closely related -y-crystallin genes (6,24).…”

The clinical and genetic heterogeneity of autosomal dominant cataract

“…We have demonstrated linkage of this pedigree to the crystallin locus on chromosome 2q (D2S157 Z max = 5.28, max = 0.00) but have discovered that this pedigree is related to the Coppock-like pedigree initially studied by Smith 15 and Harman 16 and previously linked to the crystallin gene. 17 The Coppock-like cataract phenotype is well described in the literature but no photographs of the opacity have ever been published (Fig 1f and g). …”

Congenital cataracts and their molecular genetics

“…In addition, while the pathophysiology of congenital and hereditary cataracts differs in fundamental ways from that of age related cataracts, the study of congenital cataracts can provide insights into the mechanisms of lens transparency and to some of the ways in which it can be lost as the lens ages. 2q33-q35 [103], [104], [105], [106] 123660, 123680, 601286 …”