Delineation of a complex karyotypic rearrangement by microdissection and CGH in a family affected with split foot.
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We report on a male patient and members of his family with additional material in chromosome 3. This derivative chromosome 3 was transmitted from his mother who had a complex rearrangement between chromosomes 2, 3, and 7. It was possible to delineate her chromosomal rearrangement by microdissection and reverse painting and to exclude these aberrations from being responsible for neonatal deaths and several abortions in this family. Two members of this family suffer from ectrodactyly or split hand/foot malformations (SHFM) of the feet which possibly correlates with the derivative chromosome 7 containing a breakpoint in the SHFM1 critical region involving several homeobox genes. (+info)
Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22).
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The constitutional t(11;22)(q23;q11) is the only known recurrent, non-Robertsonian translocation. To analyze the genomic structure of the breakpoint, we have cloned the junction fragments from the der(11) and der(22) of a t(11;22) balanced carrier. On chromosome 11 the translocation occurs within a short, palindromic AT-rich region (ATRR). Likewise, the breakpoint on chromosome 22 has been localized within an ATRR that is part of a larger palindrome. Interestingly, the 22q11 breakpoint falls within one of the 'unclonable' gaps in the genomic sequence. Further, a sequenced chromosome 11 BAC clone, spanning the t(11;22) breakpoint in 11q23, is deleted within the palindromic ATRR, suggesting instability of this region in bacterial clones. Several unrelated t(11;22) families demonstrate similar breakpoints on both chromosomes, indicating that their translocations are within the same palindrome. It is likely that the palindromic ATRRs produce unstable DNA structures in 22q11 and 11q23 that are responsible for the recurrent t(11;22) translocation. (+info)
The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder.
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The KE family is a large three-generation pedigree in which half the members are affected with a severe speech and language disorder that is transmitted as an autosomal dominant monogenic trait. In previously published work, we localized the gene responsible (SPCH1) to a 5.6-cM region of 7q31 between D7S2459 and D7S643. In the present study, we have employed bioinformatic analyses to assemble a detailed BAC-/PAC-based sequence map of this interval, containing 152 sequence tagged sites (STSs), 20 known genes, and >7.75 Mb of completed genomic sequence. We screened the affected chromosome 7 from the KE family with 120 of these STSs (average spacing <100 kb), but we did not detect any evidence of a microdeletion. Novel polymorphic markers were generated from the sequence and were used to further localize critical recombination breakpoints in the KE family. This allowed refinement of the SPCH1 interval to a region between new markers 013A and 330B, containing approximately 6.1 Mb of completed sequence. In addition, we have studied two unrelated patients with a similar speech and language disorder, who have de novo translocations involving 7q31. Fluorescence in situ hybridization analyses with BACs/PACs from the sequence map localized the t(5;7)(q22;q31.2) breakpoint in the first patient (CS) to a single clone within the newly refined SPCH1 interval. This clone contains the CAGH44 gene, which encodes a brain-expressed protein containing a large polyglutamine stretch. However, we found that the t(2;7)(p23;q31.3) breakpoint in the second patient (BRD) resides within a BAC clone mapping >3.7 Mb distal to this, outside the current SPCH1 critical interval. Finally, we investigated the CAGH44 gene in affected individuals of the KE family, but we found no mutations in the currently known coding sequence. These studies represent further steps toward the isolation of the first gene to be implicated in the development of speech and language. (+info)
Physical map of a conditionally dispensable chromosome in Nectria haematococca mating population VI and location of chromosome breakpoints.
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Certain isolates of the plant pathogenic fungus Nectria haematococca mating population (MP) VI contain a 1.6-Mb conditionally dispensable (CD) chromosome carrying the phytoalexin detoxification genes MAK1 and PDA6-1. This chromosome is structurally unstable during sexual reproduction. As a first step in our analysis of the mechanisms underlying this chromosomal instability, hybridization between overlapping cosmid clones was used to construct a map of the MAK1 PDA6-1 chromosome. The map consists of 33 probes that are linked by 199 cosmid clones. The polymerase chain reaction and Southern analysis of N. haematococca MP VI DNA digested with infrequently cutting restriction enzymes were used to close gaps and order the hybridization-derived contigs. Hybridization to a probe extended from telomeric repeats was used to anchor the ends of the map to the actual chromosome ends. The resulting map is estimated to cover 95% of the MAK1 PDA6-1 chromosome and is composed of two ordered contigs. Thirty-eight percent of the clones in the minimal map are known to contain repeated DNA sequences. Three dispersed repeats were cloned during map construction; each is present in five to seven copies on the chromosome. The cosmid clones representing the map were probed with deleted forms of the CD chromosome and the results were integrated into the map. This allowed the identification of chromosome breakpoints and deletions. (+info)
Chromosomal position effects reveal different cis-acting requirements for rDNA transcription and sex chromosome pairing in Drosophila melanogaster.
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In Drosophila melanogaster, the rDNA loci function in ribosome biogenesis and nucleolar formation and also as sex chromosome pairing sites in male meiosis. These activities are not dependent on the heterochromatic location of the rDNA, because euchromatic transgenes are competent to form nucleoli and restore pairing to rDNA-deficient X chromosomes. These transgene studies, however, do not address requirements for the function of the endogenous rDNA loci within the heterochromatin. Here we describe two chromosome rearrangements that disrupt rDNA functions. Both rearrangements are translocations that cause an extreme bobbed visible phenotype and XY nondisjunction and meiotic drive in males. However, neither rearrangement interacts with a specific Y chromosome, Ymal(+), that induces male sterility in combination with rDNA deletions. Molecular studies show that the translocations are not associated with gross rearrangements of the rDNA repeat arrays. Rather, suppression of the bobbed phenotypes by Y heterochromatin suggests that decreased rDNA function is caused by a chromosomal position effect. While both translocations affect rDNA transcription, only one disrupts meiotic XY pairing, indicating that there are different cis-acting requirements for rDNA transcription and rDNA-mediated meiotic pairing. (+info)
Identification of a novel gene on chromosome 7q31 that is interrupted by a translocation breakpoint in an autistic individual.
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The results of genetic linkage studies for autism have suggested that a susceptibility locus for the disease is located on the long arm of chromosome 7 (7q). An autistic individual carrying a translocation, t(7;13)(q31.3;q21), with the chromosome 7 breakpoint located in the region of 7q implicated by genetic studies was identified. A novel gene known as "RAY1" (or "FAM4A1") was found to be directly interrupted by the translocation breakpoint. The gene, which was found to be encoded by 16 exons with evidence of alternative splicing, spanned > or =220 kb of DNA at 7q31.3. Mutation screening of the entire coding region in a set of 27 unrelated autistic individuals failed to identify phenotype-specific variants, suggesting that coding region mutations are unlikely to be involved in the etiology of autism. Apparent homologues of RAY1 have also been identified in mouse, rat, pig, chicken, fruit fly, and nematode. The human and mouse genes share similar splicing patterns, and their predicted protein products are 98% identical. (+info)
A member of a gene family on Xp22.3, VCX-A, is deleted in patients with X-linked nonspecific mental retardation.
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X-linked nonspecific mental retardation (MRX) has a frequency of 0.15% in the male population and is caused by defects in several different genes on the human X chromosome. Genotype-phenotype correlations in male patients with a partial nullisomy of the X chromosome have suggested that at least one locus involved in MRX is on Xp22.3. Previous deletion mapping has shown that this gene resides between markers DXS1060 and DXS1139, a region encompassing approximately 1.5 Mb of DNA. Analyzing the DNA of 15 males with Xp deletions, we were able to narrow this MRX critical interval to approximately 15 kb of DNA. Only one gene, VCX-A (variably charged, X chromosome mRNA on CRI-S232A), was shown to reside in this interval. Because of a variable number of tandem 30-bp repeats in the VCX-A gene, the size of the predicted protein is 186-226 amino acids. VCX-A belongs to a gene family containing at least four nearly identical paralogues on Xp22.3 (VCX-A, -B, -B1, and -C) and two on Yq11.2 (VCY-D, VCY-E), suggesting that the X and Y copies were created by duplication events. We have found that VCX-A is retained in all patients with normal intelligence and is deleted in all patients with mental retardation. There is no correlation between the presence or absence of VCX-B1, -B, and VCX-C and mental status in our patients. These results suggest that VCX-A is sufficient to maintain normal mental development. (+info)
Tightly clustered 11q23 and 22q11 breakpoints permit PCR-based detection of the recurrent constitutional t(11;22).
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Palindromic AT-rich repeats (PATRRs) on chromosomes 11q23 and 22q11 at the constitutional t(11;22) breakpoint are predicted to induce genomic instability, which mediates the translocation. A PCR-based translocation-detection system for the t(11;22) has been developed with PCR primers flanking the PATRRs of both chromosomes, to examine the involvement of the PATRRs in the recurrent rearrangement. Forty unrelated carriers of the t(11;22) balanced translocation, plus two additional, independent cases with the supernumerary-der(22) syndrome, were analyzed to compare their translocation breakpoints. Similar translocation-specific junction fragments were obtained from both derivative chromosomes in all 40 carriers of the t(11;22) balanced translocation and from the der(22) in both of the offspring with unbalanced supernumerary-der(22) syndrome, suggesting that the breakpoints in all cases localize within these PATRRs and that the translocation is generated by a similar mechanism. This PCR strategy provides a convenient technique for rapid diagnosis of the translocation, indicating its utility for prenatal and preimplantation diagnosis in families including carriers of the balanced translocation. (+info)