Distal Long Arm Of Chromosome Research Articles

Localization of a Gene for Benign Adult Familial Myoclonic Epilepsy to Chromosome 8q23.3-q24.1

Benign adult familial myoclonic epilepsy is an autosomal dominant idiopathic epileptic syndrome characterized by adult-onset tremulous finger movement, myoclonus, epileptic seizures, and nonprogressive course. It was recently recognized in Japanese families. In this study, we report that the gene locus is assigned to the distal long arm of chromosome 8, by linkage analysis in a large Japanese kindred with a maximum two-point LOD score of 4.31 for D8S555 at recombination fraction of 0 (maximum multipoint LOD score of 5.42 for the interval between D8S555 and D8S1779). Analyses of recombinations place the locus within an 8-cM interval, between D8S1784 and D8S1694, in which three markers, D8S1830, D8S555, and D8S1779, show no recombination with the phenotypes. Although three other epilepsy-related loci on chromosome 8q have been recognized-one on chromosome 8q13-21 (familial febrile convulsion) and two others on chromosome 8q24 (KCNQ3 and childhood absence epilepsy)-the locus assigned here is distinct from these three epilepsy-related loci. This study establishes the presence of a new epilepsy-related locus on 8q23.3-q24.11.

Gene expression patterns in cell lines from patients with 18q- syndrome.

Some studies have suggested that for trisomies, some genes are expressed far in excess of the expected 150% level and that this "dysregulation" is one of the mechanisms for the pathogenesis of trisomies. In an attempt to generalize this result to a monosomy, we examined mRNA isolated from lymphoblastoid cell lines derived from patients with 18q- syndrome, a deletion syndrome involving loss of the distal long arm of chromosome 18. Expression levels of ten chromosome 18 genes were compared between cell lines from eight patients with 18q- syndrome and four diploid controls. Gene expression was investigated by a quantitative reverse-transcription polymerase chain reaction (RT-PCR) method. With the exception of the transcription factor NFATC1, which shows a tendency towards gene dosage compensation (the expression pattern correlates with IgA deficiency), all of the other genes were expressed at a level proportional to their gene copy number. This was true regardless of mRNA abundance or different patterns of gene expression (ubiquitous versus tissue-specific gene expression). These results indicate that, unlike dysregulated gene expression apparent in some trisomies, this monosomic syndrome is largely due to consequences of reduced gene expression.

Localization of Jacobsen Syndrome Breakpoints on a 40-Mb Physical Map of Distal Chromosome 11q

Jacobsen syndrome is a haploinsufficiency disorder caused, most frequently by terminal deletion of part of the long arm of chromosome 11, with breakpoints in 11q23.3-11q24.2. Inheritance of an expanded p(CCG)n trinucleotide repeat at the folate-sensitive fragile site FRA11B has been implicated in the generation of the chromosome breakpoint in several Jacobsen syndrome patients. The majority of such breakpoints, however, map distal to this fragile site and are not linked with its expression. To characterize these distal breakpoints and ultimately to further investigate the mechanisms of chromosome breakage, a 40-Mb YAC contig covering the distal long arm of chromosome 11 was assembled. The utility of the YAC contig was demonstrated in three ways: (1) by rapidly mapping the breakpoints from two new Jacobsen syndrome patients using FISH; (2) by demonstrating conversion to high resolution PAC contigs after direct screening of PAC library filters with a YAC clone containing a Jacobsen syndrome breakpoint; and (3) by placing 23 Jacobsen syndrome breakpoints on the physical map. This analysis has suggested the existence of at least two new Jacobsen syndrome breakpoint cluster regions in distal chromosome 11.

The 4q‐syndrome: delineation of the minimal critical region to within band 4q31

A consistent phenotype has been associated with deletion of the distal long arm of chromosome 4. An invariant requirement for the phenotype in cases described so far has been the deletion of material from within band 4q31 but few other cases have been described that further aid the delineation of the minimum critical region sufficient for the expression of the phenotype. We report a child with a small interstitial deletion within band 4q31 who exhibits most of the features of the established 4q‐phenotype.

Multiple congenital anomalies including the Rieger eye malformation in a boy with interstitial deletion of (4) (q25-->q27) secondary to a balanced insertion in his normal father: evidence for haplotype insufficiency causing the Rieger malformation.

A 7 year old boy with minor facial anomalies, the Rieger eye malformation, reduced vision, genital anomalies, and severe mental retardation had deletion of the segment 4q24-->q26. His phenotypically normal...

Detailed Physical Analysis of a 1.5-Megabase YAC Contig Containing the MXI1 and ADRA2A Genes

The distal long arm of chromosome 10 harbors genes of biomedical interest such as MXI1, a putative tumor suppressor gene, and those encoding the adrenergic receptors α2A (ADRA2A) and β1 (ADRB1). As part of a physical and genetic study of this genomic region, we constructed a 1.5-Mb YAC contig mapping to 10q25 that contains MXI1 and ADRA2A as well as a number of STSs. Rare cutting restriction site analysis of overlapping YACs allowed fine mapping of these genes and markers along the contig and revealed the presence of four CpG islands. MXI1 and ADRA2A appear to be about 600 kb apart, whereas ADRB1 is separated from ADRA2A by a distance larger than previously reported.

Hereditary neuralgic amyotrophy.

Hereditary neuralgic amyotrophy with predilection for the brachial plexus is an autosomal dominant disorder associated with recurrent, episodic, painful brachial neuropathies. Mildly dysmorphic facial features including hypotelorism, long nasal bridge and upslanting palpebral fissures are present in affected people in some pedigrees with this disease. The molecular basis of hereditary neuralgic amyotrophy is unknown and the specific gene which leads to it has not been identified. The feature of brachial neuropathy is shared with hereditary neuropathy with liability to pressure palsies, another autosomal dominant disorder which maps to chromosome 17p11.2-12 and may be clinically confused with hereditary neuralgic amyotrophy. Genetic studies have shown that the two diseases do not map to the same chromosomal region and are, therefore, genetically distinct disorders. Genetic linkage studies with polymerase chain reaction-based DNA markers in two large pedigrees recently localized the hereditary neuralgic amyotrophy gene to the distal long arm of chromosome 17 (17q24-qter).

Incorporation of 35 Novel Gene Transcripts into the Physical and Genetic Map of Human Chromosome 13

A panel of somatic cell hybrids carrying a defined set of rearrangements involving chromosome 13 has been used to assign 35 novel gene transcripts regionally. The positions of the chromosome 13 breakpoints in each somatic cell hybrid have previously been defined relative to the Généthon genetic linkage map. As a result, the position of each gene transcript has been determined relative to both the physical and the genetic linkage maps. Analysis of the distribution of these gene transcripts indicates a slight overrepresentation toward locations on the distal long arm of chromosome 13, with no localizations noted in the 13q22–q31 region. Seven of these novel gene transcripts and the gene encoding small ribonucleoprotein U6 have been mapped to YACs known to contain Généthon microsatellite markers, thereby providing further sublocalization relative to the genetic map. The positioning of these gene transcripts within the genetic and physical maps provides candidate genes for disease loci that are being mapped to the same intervals on the chromosome.

Mapping of hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) to distal chromosome 17q.

Hereditary neuralgic amyotrophy with predilection for the brachial plexus (HNA) is an autosomal dominant disorder associated with recurrent, episodic, painful brachial neuropathies. Mildly dysmorphic facial features, including hypotelorism, long nasal bridge, and upslanting palpebral fissures, are present in affected persons in some pedigrees with HNA. To determine the chromosomal location of the HNA gene, we carried out genetic linkage studies with polymerase chain reaction-based DNA markers in two large pedigrees. Linkage to markers from the distal long arm of chromosome 17 was established.

Autosomal recessive non-syndromic deafness locus (DFNB8) maps on chromosome 21q22 in a large consanguineous kindred from Pakistan.

Autosomal recessive childhood-onset non-syndromic deafness is one of the most frequent forms of inherited hearing impairment. Recently five different chromosomal regions, 7q31, 11q13.5, 13q12, 14q and the pericentromeric region of chromosome 17, have been shown to harbour disease loci for this type of neurosensory deafness. We have studied a large family from Pakistan, containing several consanguineous marriages and segregating for a recessive non-syndromic childhood-onset deafness. Linkage analysis mapped the disease locus (DFNB8) on the distal long arm of chromosome 21, most likely between D21S212 and D21S1225 with the highest lod score of 7.31 at theta = 0.00 for D21S1575 on 21q22.3.

Insulin-like growth factor I receptor expression and function in fibroblasts from two patients with deletion of the distal long arm of chromosome 15

Insulin-like growth factor I receptor expression and function in fibroblasts from two patients with deletion of the distal long arm of chromosome 15

Assignment of the Human Folate Transporter Gene to Chromosome 21q22.3 by Somatic Cell Hybrid Analysis and in Situ Hybridization

We have used the human folate transporter cDNA and a human genomic clone hybridizing to the cDNA to perform chromosomal mapping of the folate transporter gene. Human-rodent somatic cell hybrid analysis using the cDNA as the probe revealed perfect segregation with human chromosome 21. In situ hybridization of the cDNA probe to human metaphase chromosome spreads mapped the folate transporter gene to the distal long arm of chromosome 21, band q22.3. This chromosomal location was confirmed by fluorescence in situ hybridization using the genomic clone.

Chromosome 4q35 haplotypes and DNA rearrangements segregating in affected subjects of 19 Italian families with facioscapulohumeral muscular dystrophy (FSHD).

Four DNA markers on the distal long arm of chromosome 4 have been analyzed for their linkage to facioscapulohumeral muscular dystrophy locus (FSHD) in a series of 16 Italian families. We found that, in two families, the disease is not linked to the 4q35 markers, indicating the presence of genetic heterogeneity among Italian FSHD families. Linkage analysis in the remaining families supports the order cen-D4S171-D4S163-D4S139-D4S810-FSHD-qter, in agreement with the physical map from the literature. EcoRI digestion and hybridization with the distal marker p13E-11 (D4S810)1 detected DNA rearrangements in the affected members of both sporadic and familial cases of FSHD, with family-specific fragments ranging in size between 15 kb and 28 kb. In three sporadic FSHD cases, the appearance of a new "small" fragment not present in either parent was clearly associated with the development of FSHD disease. However, in the familial cases analyzed, we observed two recombinations between all four 4q35 markers and the disease locus in apparently normal subjects, leaving open the possibility of nonpenetrance of the FSHD mutation.

Localization of the gene encoding a neutral amino acid transporter-like protein to human chromosome band 19q13.3 and characterization of a simple sequence repeat DNA polymorphism.

The gene encoding a human neutral amino acid transporter-like protein (SLC1A5) was mapped to chromosome band 19q13.3 by fluorescence in situ hybridization to metaphase chromosomes. A simple sequence repeat DNA polymorphism of the form (GT)n was identified in the 3'-untranslated region of SLC1A5 mRNA. Studies in the CEPH families showed significant evidence of linkage between this DNA polymorphism and markers localized to the distal long arm of chromosome 19.

A gene for Holt–Oram syndrome maps to the distal long arm of chromosome 12

Holt-Oram syndrome (HOS) is an autosomal dominant condition of unknown origin characterized by congenital septal heart defects with associated malformations of the upper limbs (radial ray). Here, we report on the mapping of a gene causing HOS to the distal long arm of chromosome 12 (12q21-qter) by linkage analysis in nine informative families (Zmax = 6.81 at theta = 0 at the D12S354 locus). Also, multipoint linkage analysis places the HOS gene within the genetic interval between D12S84 and D12S79 (multipoint lod-score in log base 10 = 8.10). The mapping of a gene for HOS is, to our knowledge, the first chromosomal localization of a gene responsible for congenital septal heart defect in human. The characterization of the HOS gene will hopefully shed light on the molecular mechanisms that govern heart septation in the early stages of embryogenesis.

Localization of the glucagon receptor gene to human chromosome band 17q25.

The gene encoding the human glucagon receptor (GCGR) was mapped to chromosome band 17q25 by fluorescence in situ hybridization to metaphase chromosomes. An Alu variable poly(A) DNA polymorphism was identified in this gene. Studies in the CEPH families showed significant evidence of linkage between DNA polymorphism and markers localized to the distal long arm of chromosome 17.

Physical and Genetic Localization of the γ Subunit of the Cyclic GMP Phosphodiesterase on the Long Arm of Chromosome 17 (17q25)

Cyclic GMP-phosphodiesterase (PDE) is a major component of the phosphotransduction cascade that takes place in the outer segment of the rods. This heterotetrameric enzyme is composed of two large catalytic subunits ([alpha] and [beta]) and two small inhibitory [gamma] subunits. The retinal degeneration of the rd mouse has been ascribed to mutations in the [beta] subunit of the PDE complex. Until now, however, no mutations in the [gamma] subunit (PDEG) have been reported. The cDNA encoding the human PDEG has been mapped to the long arm of chromosome 17 (17q21.1). Here, the authors refine the physical mapping of the PDEG gene and provide evidence for a more distal localization (17q25) with respect to previous reports. Moreover, they present genetic data supporting the telomeric location of the gene on the distal long arm of chromosome 17. 8 refs., 2 figs.

Linkage Localization of TGFB2 and the Human Homeobox Gene HLX1 to Chromosome 1q

We have identified genetic variation within two human genes, transforming growth factor-β2 (TGFB2) and the homeobox gene HB24 (HLX1). Reported here are four human RFLPs and SSCPs for TGFB2 in humans and gorillas. In addition, we describe an RFLP and a SSCP for HLX1. We propose that HLX1 is the human homologue of the mouse homeobox gene Hlx based on extensive sequence homology between the genes and the close proximity of both genes to TGFB2 in their respective species. We also report the chromosomal localization of HLX1 to the long arm of human chromosome 1. Finally, utilizing the polymorphisms described for TGFB2 and HLX1, we have been able to localize these genes within a framework map of the distal long arm of chromosome 1 and to study the linkage relationship between these two genes. Pairwise linkage analysis shows that these two genes are linked, with a recombination fraction of 3.1% and a lod score of 14.49.

Evidence for locus heterogeneity in autosomal dominant torsion dystonia.

Idiopathic torsion dystonia (ITD) is most commonly an autosomal dominant disorder with reduced penetrance and variable expression. A locus on the distal long arm of chromosome 9 has been identified in one large non-Jewish and several Jewish families in the United States. Linkage analysis in a large Australian kindred with ITD, also containing two patients with Wilson's disease, excludes a locus for ITD in chromosome 9q34 or the region of chromosome 13 containing the Wilson disease gene. This study provides evidence for locus heterogeneity in autosomal dominant ITD and also gives additional information on gene order in chromosome 9q.

The gene for hereditary multiple exostoses does not map to the Langer-Giedion region (8q23-q24).

Hereditary multiple exostoses is a dominantly inherited skeletal disorder which alters enchondral bone during growth and is characterised by exostoses of the juxta-epiphyseal regions. Using polymorphic DNA probes, we have been able to exclude the disease gene from close proximity to the 8q24.1 region where a dominant syndrome with multiple exostoses, the trichorhinophalangeal syndrome type II (TRP II, Langer-Giedion syndrome, MIM 15025), has been previously localised (pairwise linkage Z = -8.96 at theta = 0 with probe L48 at locus D8S51). Multipoint linkage analysis using probes L48, L24, and L1 consistently excluded the HME gene from a large area of the distal long arm of chromosome 8, spanning the smallest region of overlap assigned to the TRP II gene. These studies support the clinical view that HME and TRP II are distinct entities.