Fibrosis Of Extraocular Muscles, Congenital, 2
A number sign (#) is used with this entry because congenital fibrosis of extraocular muscles type 2 (CFEOM2) is caused by mutations in the ARIX gene (602753) on chromosome 11q13.
For a general phenotypic description and a discussion of genetic heterogeneity of various forms of CFEOM, see CFEOM1 (135700)
Clinical FeaturesEngle et al. (1997) observed CFEOM in members of 3 consanguineous Saudi Arabian families and demonstrated an autosomal recessive pattern of inheritance. This form of CFEOM differed by showing features suggesting a defect in the superior and inferior divisions of the oculomotor nerve rather than in the superior division, as in CFEOM1.
MappingThe locus on chromosome 11q13 is referred to as FEOM2.
By genetic linkage analysis of the 3 Saudi Arabian families containing 18 affected individuals, Engle et al. (1997) demonstrated that the recessive form of the disease was not linked to the 'classic' CFEOM (135700) chromosome 12 locus. A genomewide screen using both individual and pooled DNA revealed linkage to markers near the centromere of 11q. Lod score analysis revealed a maximum combined lod score of 12.2 at D11S4136, with a critical region of 15 cM flanked by D11S1765 and D11S4207. Assuming allelic association secondary to founder effect, the critical region could be reduced to a 0.3-cM region within 11q13.1. Wang et al. (1998) found the same disease-associated haplotype in 2 of the 3 families, suggesting founder effect.
Engle et al. (1997) referred to the classic form as CFEOM1 and this variant form as CFEOM2. They hypothesized that CFEOM2 results from a related developmental defect affecting both the superior and inferior divisions of the oculomotor nerve and their corresponding alpha motor neurons and extraocular muscles. There is a considerable degree of homology (or paralogy) between chromosome 11 and chromosome 12: e.g., HRAS (190020) and KRAS2 (190070); IGF1 (147440) and IGF2 (147470); PTH (168450) and PTHLH (168470); etc. It may be that the existence of these clinically similar disorders, mapping to chromosome 12 and chromosome 11, respectively, have their basis in mutation in paralogous genes originating through an ancient tetraploidization of the genome.
Molecular GeneticsNakano et al. (2001) identified splice site and point mutations in the ARIX gene (see 602753.0001-602753.0003) in 4 pedigrees with CFEOM2.