A DNA Segment Encoding Two Genes Very Tightly Linked to Huntington's Disease

Gilliam, T. Conrad; Bućan, Maja; MacDonald, Marcy E.; Zimmer, Michael; Haines, Jonathan L.; Cheng, Shirley V.; Pohl, Thomas; Meyers, Richard H.; Whaley, William L.; Allitto, Bernice A.; Faryniarz, Anne G.; Wasmuth, John J.; Frischauf, Anna Maria; Conneally, P. Michael; Lehrach, Hans; Gusella, James F.

doi:10.1126/science.2890209

Cited by 91 publications

(27 citation statements)

References 10 publications

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“…D4S43 is a polymorphic locus identified in humans that is closely linked to the Huntington's disease gene (HD) on human chromosome 4p (Gilliam et al 1987;S.V. Cheng et al, in prep.).…”

Section: Discussionmentioning

confidence: 99%

A new family of mouse homeo box-containing genes: molecular structure, chromosomal location, and developmental expression of Hox-7.1.

Hill¹,

Jones²,

Rees³

et al. 1989

Genes Dev.

378

175

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Two families of homeo box-containing genes have been identified in mammals to date, the Antennapedia-and engrailed-like homeo boxes, based on the sequence similarity to those from Drosophila. Here, we report the isolation of a homeo box-containing gene that belongs to a new family of which there are at least three related genes in the mouse genome. The homeo box of this new gene shows remarkable similarity to the Drosophila Msh homeo box that we designate as the prototype for this family. The gene maps to the proximal end of mouse chromosome 5 and does not cosegregate with any known homeo box-containing gene. We designate this locus Hox-7.1. In situ hybridizations to mouse embryos at different stages show a unique pattern of expression, as compared to other homeo box-containing genes described thus far. Hox-7.1 transcripts are detected in 9.5-dayold embryos in the neural crest, developing limb bud, and visceral arches. Later, this gene is expressed in regions of the face that are derived from neural crest and in the interdigital mesenchymal tissues in both the fore-and hindlimbs.

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“…D4S43 is a polymorphic locus identified in humans that is closely linked to the Huntington's disease gene (HD) on human chromosome 4p (Gilliam et al 1987;S.V. Cheng et al, in prep.).…”

Section: Discussionmentioning

confidence: 99%

A new family of mouse homeo box-containing genes: molecular structure, chromosomal location, and developmental expression of Hox-7.1.

Hill¹,

Jones²,

Rees³

et al. 1989

Genes Dev.

378

175

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“…Therefore, we conclude that genes that contribute to the WHS phenotype reside in the interval distal to D4S43 and proximal to D4S168. This localization effectively eliminates several genes (MYL5, ZNF141, PDE␤, and IDUA) mapped to 4p16.3 previously suggested as having a role in the etiology of WHS.Several potentially expressed sequences have been found throughout the WHSCR but these have not been studied in detail [Gilliam et al, 1987;John et al, 1994;Rommens et al, 1993;Snell et al, 1993]. The exception is the FGFR3 gene, located near the distal end of the refined WHSCR, FGFR3 has been studied both for its role in a number of growth related disorders [Bellus et al, 1995;Meyers et al, 1995;Shiang et al, 1994;Tavormina et al, 1995].…”

mentioning

confidence: 94%

“…Owing to the abundant cloned resources from this region of the genome, a large number of potential coding sequences were identified [Gilliam et al, 1987;John et al, 1994;Rommens et al, 1993;Snell et al, 1993]. Overall, the region appears to be gene dense.…”

Section: Introductionmentioning

confidence: 99%

Delimiting the Wolf-Hirschhorn syndrome critical region to 750 kilobase pairs

et al. 1997

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Wolf-Hirschhorn syndrome (WHS) is a multiple anomaly condition characterized by mental and developmental defects, resulting from the absence of the distal segment of one chromosome 4 short arm (4p16.3). Owing to the complex and variable expression of this disorder, it is thought that the WHS is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. The 2.2 Mbp genomic segment previously defined as the critical region by the analyses of patients with terminal or interstitial deletions is extremely gene dense and an intensive investigation of the developmental role of all the genes contained within it would be daunting and expensive. Further refinement in the definition of the critical region would be valuable but depends on available patient material and accurate clinical evaluation. In this study, we have utilized fluorescence in situ hybridization to further characterize a WHS patient previously demonstrated to have an interstitial deletion and demonstrate that the distal breakpoint occurs between the loci FGFR3 and D4S168. This reduces the critical region for this syndrome to less than 750 kbp. This has the effect of eliminating several genes previously proposed as contributing to this syndrome and allows further research to focus on a more restricted region of the genome and a limited set of genes for their role in the WHS syndrome.

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“…The genetic distance between D4SJ0 and HD is estimated at 3 centimorgans (cM), with 95% confidence limits of0.8-6 cM (8). On the average, 1 cM of genetic distance corresponds to p1000 kilobases (kb) of physical distance (9), but the rarity of DNA sequences in a chromosome 4 library that map distal to D4S10 (10,11) and the observed increase in chiasma formation near the telomeres of most autosomes (12) suggest that the physical distance between D4SJO and HD might well be <3000 kb.…”

mentioning

confidence: 99%

“…Very recently, another DNA marker, D4S43, has been identified that maps distal to D4SJO and is therefore either closer to HD on the same side or is a flanking marker (11). Its distance from HD is estimated to be 0-1.5 cM.…”

mentioning

confidence: 99%

Chromosome jumping from D4S10 (G8) toward the Huntington disease gene.

Richards

Gilliam

Cole

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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The gene for Huntington disease (HD) has been localized to the distal portion of the short arm of human chromosome 4 by linkage analysis. Currently, the two closest DNA markers are D4S1O (G8), located "p3 centimorgans centromeric to HD, and D4S43 (C4H), positioned 0-1.5 centimorgans from HD. In an effort to move closer to the HD gene, with the eventual goal of identifying the gene itself, we have applied the technique of chromosome jumping to this region. A 200-kilobase jumping library has been constructed, and ajump from D4S1O has been obtained and its approximate distance verified by pulsed field gel electrophoresis. Two restriction fragment length polymorphisms have been identified at the jump locus, which is denoted D4S81. Linkage analysis of previously identified recombinants between D4S1O and HD or D4S1O and D4S43 shows that in two of five events the jump has crossed the recombination points. This unequivocally orients D4S1O and D4S81 on the chromosome, provides additional markers for HD, and suggests that recombination frequency in this region of chromosome 4 may be increased, so that the physical distance from D4S1O to HD may not be as large as originally suspected.A large number of human disorders are caused by mutations in single genes whose normal function, despite intensive investigation, is unknown. Recently, it has become possible to attempt the cloning of such genes by a process called " reverse genetics," in which the gene is identified primarily by its map position in the genome rather than by direct knowledge of its protein product (1, 2). Huntington disease (HD) is an autosomal dominant neurodegenerative condition with a wide range in age of onset (3, 4). The motor manifestations include incoordination and involuntary movements (chorea). Psychiatric features of forgetfulness, personality changes, depression, and eventual dementia are characteristic. Anatomically, the most pronounced changes are neuronal loss in the basal ganglia of the brain, especially the caudate nucleus; thus far, however, no specific protein abnormality has been found.HD has been found to be tightly linked (5) to the DNA marker D4SJ0 (G8), which has been mapped by in situ hybridization (6) and somatic cell genetics (7) (13) and independently by Poutska and Lehrach (14), depends on the circularization of very large DNA fragments, followed by cloning of the junction fragments of these circles, which bring together DNA sequences that were originally located a considerable distance apart in the genome. We have previously demonstrated the successful application of this technique to a jump of 100 kb in the cystic fibrosis region (15). In this report, we describe the construction of a 200-kb jumping library and its successful utilization to move closer to the HD gene from D4S10.MATERIALS AND METHODS Cell Line. HHW661 is a somatic cell hybrid carrying a selectable human t(4;5) (p15.1;pl5.1) translocation chromosome as its only human DNA (16

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A DNA Segment Encoding Two Genes Very Tightly Linked to Huntington's Disease

Cited by 91 publications

References 10 publications

A new family of mouse homeo box-containing genes: molecular structure, chromosomal location, and developmental expression of Hox-7.1.

A new family of mouse homeo box-containing genes: molecular structure, chromosomal location, and developmental expression of Hox-7.1.

Delimiting the Wolf-Hirschhorn syndrome critical region to 750 kilobase pairs

Chromosome jumping from D4S10 (G8) toward the Huntington disease gene.

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