28 research outputs found
Positional cloning of an X;8 translocation (p22.13;q22.1) associated with multiple exostoses and autism
Autism is characterized by qualitative impairments in communication and reciprocal social interaction. About 3 in 10,000 in the general population suffer from this neurodevelopmental disorder. The majority of patients also manifest mental retardation and about 20-45% epilepsy. Multiple exostoses is the commonest form of all skeletal dysplasias, affecting 1 in 50,000 live births. The condition, characterized by cartilaginous protuberances at the ends of the diaphyses, affects the extremities causing skeletal deformities and short stature. Autism and multiple exostoses are considered to be inherited disorders, but the underlying biochemical defects of the disorders are unknown. Both of these conditions allow for survival but considerably diminish the quality of life. An X;8 translocation was identified in a female patient, ML, with autism and multiple exostoses. Her phenotypic manifestations are likely due to the chromosomal abnormality. A positional candidate cloning strategy was used to investigate the genes involved in the translocation. The translocation breakpoint was first isolated in Yeast Artificial Chromosomes (YACs), then in cosmid and plasmid clones. The translocation was reciprocal within a 5'-GGCA-3' sequence found on both X and 8 chromosomes without gain or loss of a single nucleotide. The translocation breakpoint on the X chromosome occurred in the first intron of the gastrin releasing peptide receptor (GRPR) gene and on chromosome 8 approximately 30 kb distal to the 3' end of the Syndecan-2 gene (SDC2), also known as human heparan sulfate proteoglycan or fibroglycan. Although the GRPR gene was shown to escape X-inactivation and the coding region of the SDC2 gene was not disrupted, a dosage effect of the GRPR gene and a position effect of the SDC2 gene may, however, have contributed to the phenotype observed in this patient. The orientation of these genes with respect to the translocation was incompatible with the formation of a fusion gene. The GRPR and SDC2 genes may provide insight into the biochemical nature of autism and multiple exostoses. Investigation of mutations in these two genes in unrelated patients with either autism or multiple exostoses as well as linkage and association studies are needed to validate them as candidate genes.</p
Positional cloning of an X; 8 translocational (p22.12; q22.1) associated with multiple exostoses and autism
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Autism and multiple exostoses associated with an X;8 translocation occurring within the GRPR gene and 3' to the SDC2 gene
Fluorescence in situ hybridisation of multiple probes on a single microscope slide.
We report a method to analyse multiple samples by fluorescence in situ hybridisation on a single glass microscope slide. Wells were formed in which independent hybridisation reactions could proceed by sealing a silicon rubber gasket to the slide. In the largest format tested, different probes were hybridised simultaneously by applying them directly from a 96-well microtitre dish which was inverted on a glass plate. This technique will increase the rate of analysis of multiple probes against a standard set of chromosomes and could also be used to analyse different karyotypes using a panel of probes such as single chromosome paints during a single operation. It should be useful for both chromosomal mapping projects and screening for chromosome abnormalities in clinical diagnostic laboratories
Characterization of a 1.0 Mb YAC contig spanning two chromosome breakpoints related to Menkes disease.
Menkes disease, an X-linked recessive disorder of copper metabolism, has recently been mapped to Xq13.3 by two Menkes patients carrying chromosome rearrangements within this region. The breakpoints have been investigated by nonisotopic in situ suppression hybridization using YACs isolated from this region with the flanking markers DXS56 and PGK1. Three YACs were extending over the breakpoints at Xq13.3 and were shown to be overlapping by partial digest restriction maps, IRS-PCR fingerprinting and by the presence of common cosmid clones. These cosmids were subcloned and one of the single copy probes detected both breakpoints using rare-cutting restriction enzyme digests of the patients. All the results together localize the breakpoints to about 100 kb within the overlapping region of the YACs. Mapping of both breakpoints in a 1 Mb YAC contig implies that these YACs contain at least partially, the gene responsible for Menkes disease
Autism, mental retardation, multiple exostoses and short stature in a female with 46,X,t(X;8)(p22.13;q22.1).
A young adult female with multiple exostoses, short stature, autism, mental retardation and 46,X,t(X;8)(p22.13;q22.1) is described. Although the clinical features and translocation breakpoints raise the possibility of a number of specific conditions, the constellation of problems is not consistent with any previously reported genetic syndrome. It is argued that her clinical disorder is likely due to the chromosomal abnormality and that further detailed molecular genetic investigation may shed light on the genetic basis to various components of her phenotype including the autism
Construction of a YAC contig spanning the Xq13.3 subband.
The loci involved in several X-linked mental retardation syndromes have been linked to the pericentromeric region of the X chromosome long arm (Xq12-q21). To isolate candidate genes for these diseases, we set up the construction of YAC contigs spanning this region. Two of these syndromes (the Juberg-Marsidi syndrome and the alpha-thalessemia mental retardation syndrome) have been recently linked, with high lod scores, to polymorphic probes previously assigned to Xq13.3. We therefore constructed a first YAC contig, encompassing this band, from DXS441 to PGK1. The physical map, deduced from the isolated clones, extends over 2.1 Mb of genomic DNA. Restriction analysis of the YAC contig allowed us to map precisely the loci previously assigned to that chromosomal region and to define their relative order. The validity of this physical map has been checked by comparing Sfi I digests of the YACs to genomic fragments obtained with the same enzyme. A cDNA selection approach, already performed with a previous partial contig, has been extended to cover the whole region
Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein.
Menkes disease is a lethal-X linked recessive disorder associated with copper metabolism disturbance. We have recently mapped two chromosome breakpoints related to this disease in a 1 megabase yeast artificial chromosome contig at Xq13.3. We now report the construction of a phage contig and the isolation of candidate partial cDNAs for the Menkes disease gene. The candidate gene expresses an 8 kb message in all investigated tissues, and deletions were detected in 16% of 100 unrelated Menkes patients. The deduced partial protein sequence shared the GMTCXXC motif with bacterial metal resistance operons, suggesting a potential heavy metal binding protein. These findings should lead to more accurate prenatal diagnosis of this severe disease and a better understanding of the cellular homeostasis of essential heavy metals
Autism and multiple exostoses associated with an X;8 translocation occurring within the GRPR gene and 3' to the SDC2 gene.
An X;8 translocation was identified in a 27-year-old female patient manifesting multiple exostoses and autism accompanied by mental retardation and epilepsy. Through molecular analysis using yeast artificial chromosomes (YACs) and cosmid clones, the translocation breakpoint was isolated and confirmed to be reciprocal within a 5'-GGCA-3' sequence found on both X and 8 chromosomes without gain or loss of a single nucleotide. The translocation breakpoint on the X chromosome occurred in the first intron of the gastrin-releasing peptide receptor (GRPR) gene and that on chromosome 8 occurred approximately 30 kb distal to the 3' end of the Syndecan-2 gene (SDC2), also known as human heparan sulfate proteoglycan or fibroglycan. The GRPR gene was shown to escape X-inactivation. A dosage effect of the GRPR and a position effect of the SDC2 gene may, however, contribute the phenotype observed in this patient since the orientation of these genes with respect to the translocation was incompatible with the formation of a fusion gene. Investigation of mutations in these two genes in unrelated patients with either autism or multiple exostoses as well as linkage and association studies is needed to validate them as candidate genes
Construction of a YAC contig spanning the Xq13.3 subband.
International audienceThe loci involved in several X-linked mental retardation syndromes have been linked to the pericentromeric region of the X chromosome long arm (Xq12-q21). To isolate candidate genes for these diseases, we set up the construction of YAC contigs spanning this region. Two of these syndromes (the Juberg-Marsidi syndrome and the alpha-thalessemia mental retardation syndrome) have been recently linked, with high lod scores, to polymorphic probes previously assigned to Xq13.3. We therefore constructed a first YAC contig, encompassing this band, from DXS441 to PGK1. The physical map, deduced from the isolated clones, extends over 2.1 Mb of genomic DNA. Restriction analysis of the YAC contig allowed us to map precisely the loci previously assigned to that chromosomal region and to define their relative order. The validity of this physical map has been checked by comparing Sfi I digests of the YACs to genomic fragments obtained with the same enzyme. A cDNA selection approach, already performed with a previous partial contig, has been extended to cover the whole region