7 research outputs found
A YAC contig in Xp21 containing the adrenal hypoplasia congenita and glycerol kinase deficiency genes
The gene loci for adrenal hypoplasia congenita (AHC) and glycerol kinase deficiency (GK) map in Xp21 distal to Duchenne muscular dystrophy (DMD), and proximal to DXS28 (C7), by analysis of patient deletions. We have constructed a yeast artificial chromosome (YAC) contig encompassing a 1.2 Mb region extending distally from DMD, and containing DXS708 (JC-1), the distal junction clone of a patient with GK and DMD. A pulsed-field gel electrophoresis map of the YAC contig identified 3 potential CpG islands. Whole YAC hybridization identified cosmids both for construction of cosmid contigs, and isolation of single copy probes. Thirteen new single copy probes and DXS28 and DXS708 were hybridized on a panel of patients; the deletion mapping indicates that the YAC contig contains both GK and at least part of AHC, and together with the physical map defines a GK critical region of 50-250 kb. In one AHC patient with a cytogenetically detectable deletion we used the new probes to characterize a complex double deletion. Non-overlapping deletions observed in other unrelated AHC patients indicate that the AHC gene is large, extending over at least 200-500 kb. This mapping provides the basis for the identification of the AHC and GK gene
A YAC contig in Xp21 containing the adrenal hypoplasia congenita and glycerol kinase deficiency genes
The gene loci for adrenal hypoplasia congenita (AHC) and glycerol kinase deficiency (GK) map in Xp21 distal to Duchenne muscular dystrophy (DMD), and proximal to DXS28 (C7), by analysis of patient deletions. We have constructed a yeast artificial chromosome (YAC) contig encompassing a 1.2 Mb region extending distally from DMD, and containing DXS708 (JC-1), the distal junction clone of a patient with GK and DMD. A pulsed-field gel electrophoresis map of the YAC contig identified 3 potential CpG islands. Whole YAC hybridization identified cosmids both for construction of cosmid contigs, and isolation of single copy probes. Thirteen new single copy probes and DXS28 and DXS708 were hybridized on a panel of patients; the deletion mapping indicates that the YAC contig contains both GK and at least part of AHC, and together with the physical map defines a GK critical region of 50-250 kb. In one AHC patient with a cytogenetically detectable deletion we used the new probes to characterize a complex double deletion. Non-overlapping deletions observed in other unrelated AHC patients indicate that the AHC gene is large, extending over at least 200-500 kb. This mapping provides the basis for the identification of the AHC and GK gene
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