The genes for X-linked ocular albinism (OA1) and microphthalmia with linear skin defects (MLS): cloning and characterization of the critical regions

Abstract

We have used cell lines from patients with deletions and translocations involving the Xp22 region to map the genes for two X-linked disorders, ocular albinism type 1 (OA1) and microphthalmia with linear skin defects (MLS). Using existing and newly isolated DNA markers, the map position within Xp22 of key patient breakpoints, defining the boundaries of the genomic regions involved in these disorders (the critical regions), has been precisely determined. A 2.6 Mb yeast artificial chromosome (YAC) contig, spanning the critical regions for these two disorders, was assembled. Detailed long-range restriction analysis of the contig established the sizes of the critical regions to be 200 kb for OA1 and 800 - 925 kb for MLS. Ten potential CpG-islands, representing candidate sites for genes, have been mapped within the 2.6 Mb region. Our data should greatly facilitate efforts aimed at cloning the genes for these developmental defects.

Choroid Plexus Papilloma and Cysts in the Aicardi Syndrome: Case Reports

“…chorioretinal abnormalities, microphthal mia, callosal agenesis, seizures, and mental retardation) with the microphthalmia with linear skin defects syn drome [20,21]. Similar to Aicardi syndrome, this disease is X-linked and the MLS chromosomal locus has been specifically mapped to Xpter to Xp22 [22,23], The puta- five gene affected in MLS has been cloned and is homolo gous to mitochondrial holocytochrome c-type synthetases identified in other organisms [24], Schaefer et al [24] per formed a mutational analysis of the human holocyto chrome c-type synthetase (HCCS) gene in lymphoblasts derived from 7 Aicardi syndrome patients. No evidence of gene rearrangements or mutations was seen.…”

Microphthalmia with linear skin defects syndrome (MLS): a male with a mosaic paracentric inversion of Xp

“…To map the putative inversion breakpoint in Xp22.3 more precisely, we performed FISH analysis with YAC clone 225H10, which contains part of the previously defined MLS critical region (Wapenaar et al, 1993) and which has been found to be deleted in three patients with MLS syndrome (Lindsay et al, 1994). In the majority of the 38 metaphases analyzed with YAC 225H10, we observed one distinct signal on the short arm of the X chromosome (Fig.…”

“…By mapping the breakpoints of MLS patients, an F 570-kb minimal region of monosomy has been identified in Xp22.3 (Wapenaar et al, 1993;, distal to AMELX (amelogenin) (Lagerstrom et al, 1991), and cloned into overlapping cosmids (Cox et al, 1998). Three genes have been mapped and characterized in the critical deletion interval for MLS: MID1 (midline-1) mutated in the X-linked Opitz G/BBB syndrome (Quaderi et al, 1997), HCCS which encodes the human holocytochrome c-type synthetase (Schaefer et al, 1996), and ARH-GAP6 encoding a Rho GTPase activating protein (Schaefer et al, 1997).…”

A very high density microsatellite map (1 STR / 41 kb) of 1.7 Mb on Xp22 spanning the microphthalmia with linear skin defects (MLS) syndrome critical region

“…6,8,9 Based on the molecular characterisation of the chromosomal abnormalities in MLS patients, a 0.6 Mb genomic region was reported to contain all or part of the disease gene(s). 10,11 Here we report the near-complete and fully annotated cosmid contig covering approximately 1.7 Mb distal to Amelogenin and encompassing the critical region for MLS. Over 40 new polymorphic repeat markers have been developed and these, together with all relevant anchor STS markers from the larger linkage and YAC-based physical maps.…”