Recombination of 4p 16 DNA markers in an unusual family with Huntington disease

Catrin Pritchard, Ning Zhu, Jian Zuo, Laura Bull, Margaret A Pericak-Vance, Jeffery M Vance, Allen D. Roses, Athena Milatovich, Uta Francke, David R. Cox, Richard M. Myers

Research output: Contribution to journalArticle

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Abstract

The Huntington disease (HD) mutation has been localized to human chromosome 4p16, in a 6-Mb region between the D4S10 locus and the 4p telomere. In a report by Robbins et al., a family was identified in which an affected individual failed to inherit three alleles within the 6-Mb region originating from the parental HD chromosome. To explain these results, it was suggested that the HD locus (HD) lies close to the telomere and that a recombination event took place between HD and the most telomeric marker examined, D4S90. As a test of this telomere hypothesis, we examined six members of this family, five of whom are affected with HD, for the segregation of 12 polymorphic markers from 4p16, including D4S169, which lies within 80 kb of the 4p telomere. We separated, in somatic cell hybrids, the chromosomes 4 from each family member, to determine the phase of marker alleles on each chromosome. We excluded nonpaternity by performing DNA fingerprint analyses on all six family members, and we found no evidence for chromosomal rearrangements when we used high-resolution karyotype analysis. We found that two affected siblings, includ-ing one of the patients originally described by Robbins et al., inherited alleles from the non-HD chromosome 4 of their affected parents, throughout the 6-Mb region. We found that a third affected sibling, also studied by Robbins et al., inherited alleles from the HD chromosome 4 of the affected parent, throughout the 6-Mb region. Finally, we found that a fourth sibling, who is likely affected with HD, has both a recombination event within the 6-Mb region and an additional recombination event in a more centromeric region of the short arm of chromosome 4. Our results argue against a telomeric location for HD and suggest that the HD mutation in this family is either associated with DNA predisposed to double recombination and/or gene conversion within the 6-Mb region or is in a gene that is outside this region and that is different from that mutated in most other families with HD.

Original languageEnglish
Pages (from-to)1218-1230
Number of pages13
JournalAmerican Journal of Human Genetics
Volume50
Issue number6
StatePublished - Jun 1 1992
Externally publishedYes

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Huntington Disease
Genetic Markers
Genetic Recombination
Chromosomes, Human, Pair 4
Telomere
Alleles
Siblings
Chromosomes
Gene Conversion
Mutation
DNA Fingerprinting
Hybrid Cells
Human Chromosomes
Karyotype
Parents

ASJC Scopus subject areas

  • Genetics

Cite this

Recombination of 4p 16 DNA markers in an unusual family with Huntington disease. / Pritchard, Catrin; Zhu, Ning; Zuo, Jian; Bull, Laura; Pericak-Vance, Margaret A; Vance, Jeffery M; Roses, Allen D.; Milatovich, Athena; Francke, Uta; Cox, David R.; Myers, Richard M.

In: American Journal of Human Genetics, Vol. 50, No. 6, 01.06.1992, p. 1218-1230.

Research output: Contribution to journalArticle

Pritchard, C, Zhu, N, Zuo, J, Bull, L, Pericak-Vance, MA, Vance, JM, Roses, AD, Milatovich, A, Francke, U, Cox, DR & Myers, RM 1992, 'Recombination of 4p 16 DNA markers in an unusual family with Huntington disease', American Journal of Human Genetics, vol. 50, no. 6, pp. 1218-1230.
Pritchard, Catrin ; Zhu, Ning ; Zuo, Jian ; Bull, Laura ; Pericak-Vance, Margaret A ; Vance, Jeffery M ; Roses, Allen D. ; Milatovich, Athena ; Francke, Uta ; Cox, David R. ; Myers, Richard M. / Recombination of 4p 16 DNA markers in an unusual family with Huntington disease. In: American Journal of Human Genetics. 1992 ; Vol. 50, No. 6. pp. 1218-1230.
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abstract = "The Huntington disease (HD) mutation has been localized to human chromosome 4p16, in a 6-Mb region between the D4S10 locus and the 4p telomere. In a report by Robbins et al., a family was identified in which an affected individual failed to inherit three alleles within the 6-Mb region originating from the parental HD chromosome. To explain these results, it was suggested that the HD locus (HD) lies close to the telomere and that a recombination event took place between HD and the most telomeric marker examined, D4S90. As a test of this telomere hypothesis, we examined six members of this family, five of whom are affected with HD, for the segregation of 12 polymorphic markers from 4p16, including D4S169, which lies within 80 kb of the 4p telomere. We separated, in somatic cell hybrids, the chromosomes 4 from each family member, to determine the phase of marker alleles on each chromosome. We excluded nonpaternity by performing DNA fingerprint analyses on all six family members, and we found no evidence for chromosomal rearrangements when we used high-resolution karyotype analysis. We found that two affected siblings, includ-ing one of the patients originally described by Robbins et al., inherited alleles from the non-HD chromosome 4 of their affected parents, throughout the 6-Mb region. We found that a third affected sibling, also studied by Robbins et al., inherited alleles from the HD chromosome 4 of the affected parent, throughout the 6-Mb region. Finally, we found that a fourth sibling, who is likely affected with HD, has both a recombination event within the 6-Mb region and an additional recombination event in a more centromeric region of the short arm of chromosome 4. Our results argue against a telomeric location for HD and suggest that the HD mutation in this family is either associated with DNA predisposed to double recombination and/or gene conversion within the 6-Mb region or is in a gene that is outside this region and that is different from that mutated in most other families with HD.",
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AU - Vance, Jeffery M

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