Mapping studies on a pericentric inversion (18) (p11.31 q21.1) in a family with both schizophrenia and learning disability.

Chromosomal abnormalities that co-occur with psychiatric disorders can be useful direct pointers to the locus of susceptibility genes. Two families with pericentric inversions of chromosome 18, inv 18(p11.3 q21.1) and psychiatric illness have previously been described. We have fine mapped the chromosomal breakpoints of the rearrangement in a clinically well, inversion carrier from one of these families where other inversion carriers suffered from chronic schizophrenia or severe learning disability. Yeast artificial chromosomes (YACs) from the Whitehead/MIT physical maps of human chromosome 18 have been positioned relative to the chromosomal breakpoints and a number of YACs that span these breakpoints have been identified. Linkage and association studies have previously suggested these regions of chromosome 18q and 18p as candidate loci harbouring genes involved in bipolar disorder and schizophrenia.

Genomic organization of the human TIMP-1 gene. Investigation of a causative role in the pathogenesis of X-linked retinitis pigmentosa 2.

PURPOSE: To evaluate the role of TIMP-1 in inherited retinal degeneration. METHODS: The genomic structure of the TIMP-1 gene was established and male patients with x-linked retinitis pigmentosa 2 from five families were screened for sequence alterations by direct sequencing in all exons, exon-intron boundaries, and the 5' upstream region of the gene. RESULTS: TIMP-1 appears to be expressed in the retina at low levels and consists of six exons spanning a genomic region of approximately 4.5 kb on Xp11.23. No disease-specific sequence alterations were identified. A site substitution in exon 5 was observed in samples from control subjects and patients, but it did not alter the amino acid sequence of the protein product. CONCLUSIONS: The results of this study exclude mutations in the TIMP-1 coding sequence, splice sites, and the 5' upstream region as a cause of retinal degeneration in x-linked retinitis pigmentosa 2. However, an as yet unidentified regulatory element that lies outside these intervals may be implicated. The role of this tightly regulated protein in the normal functioning of the retina has yet to be determined.

Mapping the RP2 locus for X-linked retinitis pigmentosa on proximal Xp: a genetically defined 5-cM critical region and exclusion of candidate genes by physical mapping.

Genetic linkage studies have implicated at least two loci for X-linked retinitis pigmentosa (XLRP) on proximal Xp. We now report a defined genetic localization for the RP2 locus to a 5-cM interval in Xp11.3-11.23. Haplotype analysis of polymorphic markers in recombinant individuals from two XLRP families has enabled us to identify DXS8083 and DXS6616 as the new distal and proximal flanking markers for RP2. Using STS-content and YAC end-clone mapping, an approximately 1.2 Mb YAC contig has been established encompassing the proximal RP2 boundary and extending from T1MP1 to DXS1240 in Xp11.23. Several ESTs have been positioned and ordered on this contig, one of which is novel to the region, identified by sequence data-base match to a physically mapped YAC insert terminal STS. Integration of the genetic and physical data has placed four retinally expressed genes proximal to DXS6616, and thereby excluded them from a causitive role in RP2. This work now provides a much needed focus for positional cloning approaches to isolation of the defective gene.

Physical mapping within the tuberous sclerosis linkage group in region 9q32-q34.

Pulsed-field gel electrophoresis and flow dot-blot analysis have been used to construct a physical map of the q32-q34 region of chromosome 9, where one of the loci responsible for tuberous sclerosis (TSC1) has been mapped by genetic linkage. Five linked groups of markers have been defined by pulsed-field gel electrophoresis. The orientation of these groups and the order of markers within them were determined by hybridization to flow-sorted dot blots derived from a panel of cell lines of chromosome 9 translocations to place probes proximal or distal to each breakpoint. The local map order in 9q32-q34 derived by application of this combination of techniques is as follows: centromere-ALAD-1.3 Mb-ORM/20 kbD9S16-GSN-250 kb-C5-HXB-1.9 Mb-D9S21-AK1-1.4 Mb-SPTAN1-ASS-800 kb-ABL-2 Mb-D9S10/350 Kb/DBH-telomere.