Novel mutation and three other sequence variants segregating with phenotype at keratoconus 13q32 susceptibility locus

Abstract

Keratoconus (KTCN), a non-inflammatory corneal disorder characterized by stromal thinning, represents a major cause of corneal transplantations. Genetic and environmental factors have a role in the etiology of this complex disease. Previously reported linkage analysis revealed that chromosomal region 13q32 is likely to contain causative gene(s) for familial KTCN. Consequently, we have chosen eight positional candidate genes in this region: MBNL1, IPO5, FARP1, RNF113B, STK24, DOCK9, ZIC5 and ZIC2, and sequenced all of them in 51 individuals from Ecuadorian KTCN families and 105 matching controls. The mutation screening identified one mutation and three sequence variants showing 100% segregation under a dominant model with KTCN phenotype in one large Ecuadorian family. These substitutions were found in three different genes: c.2262A4C (p.Gln754His) and c.720+43A4G in DOCK9; c.2377-132A4C in IPO5 and c.1053+29G4C in STK24. PolyPhen analyses predicted that c.2262A4C (Gln754His) is possibly damaging for the protein function and structure. Our results suggest that c.2262A4C (p.Gln754His) mutation in DOCK9 may contribute to the KTCN phenotype in the large KTCN-014 family.

Keratoconus: an inflammatory disorder?

“…51,52 Some of the genes with reported mutations are SOD1 (locus 21q22.11), VSX1 (locus 20p11.2), and DOCK9 (locus 13q32), which regulate the expression of superoxide dismutase (SOD), photoreceptor cells, and G protein, respectively. [53][54][55] Recently, mutations in MIR184 have been identified as an uncommon cause of keratoconus. 55,56 LOX (locus 5q23.2), the gene encoding lysyl oxidase (LOX) enzyme, which is involved in collagen and elastin cross-linking, have also been related to keratoconus.…”

The pathogenesis of keratoconus

“…Unfortunately, convincing KC-associated genes have not been identified within these reported loci, with one notable exception; the identification of a potentially pathogenic variant in candidate gene DOCK9, segregating in a large dominant KC family of Ecuadorian origin. 78 There are several reasons for this lack of identification of causative genes from linkage studies. Using conventional linkage strategies to understand complex diseases relies on the assumption that the condition is caused by a variant that has a large effect, and this may be an over-interpretation of familial aggregation of KC in many instances.…”

Collagen synthesis disruption and downregulation of core elements of TGF-β, Hippo, and Wnt pathways in keratoconus corneas

“…[5][6][7] Also, numerous sequence variants in our KTCN research were identified. [8][9][10][11][12] However, because variations in these genes were specific to particular families or populations only, they could not be recognized as causative for KTCN in the general population. The one possible explanation for the absence of genetic KTCN marker(s) is that the studied genes constitute only a minor fraction of the total genetic load and the number of genes altered in KTCN may be higher.…”