Mitotic stability and meiotic variability of the (CAG)n repeat in the huntington disease gene

Christine Zühlke; Olaf Riess; Barbara Bockel; Herwlg Lange; Ulrike Thies

doi:10.1093/hmg/2.12.2063

Mitotic stability and meiotic variability of the (CAG)_n repeat in the huntington disease gene

Christine Zühlke^*, Olaf Riess, Barbara Bockel, Herwlg Lange, Ulrike Thies

^*Corresponding author for this work

Institute of Human Genetics

144 Citations (Scopus)

Abstract

The gene causing Huntingtons's disease, an autosomal dominantly Inherited, neurodegenerative disorder, has been Identified recently. The corresponding mutation Is Involving an expansion In the number of (CAG)_n repeats In the coding region of the Huntington's disease gene on chromosome 4. In this report, we demonstrate the length variation of the repeat In 513 non-HD chromosomes from normal Individuals and HD patlents showing 23 alleles with 11 to 33 repeats. Analyzing the Inherltance of the (CAG)_n stretch we found melotic instability for HD alleles ([CAG]₄₀ to [CAG]₇₅) with a mutation frequency of approximately 0.7, while In 431 meloses of normal alleles only two expanslons were Identified. The risk of expansion during spermatogenesis is enhanced compared to oogenesls explaining juvenile onset by transmission from affected fathers. Further, the number of (CAG)_n copies In an affected individual In relation to the sex of the transmitting parent was evaluated and no significant differences were found. No mosalcism or differences In the repeat lengths were observed In the DNA from different tissues Including brain and lymphocytes of two HD patients indicating mltotic stability of the mutation. Therefore, the determination of the repeat number In the DNA of blood lymphocytes Is probably representative of all tissues In a patient.

Original language	English
Journal	Human Molecular Genetics
Volume	2
Issue number	12
Pages (from-to)	2063-2067
Number of pages	5
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/2.12.2063
Publication status	Published - 12.1993

Funding

We would li e to thank the patients, their families and clinicians, whose cooperation was essential in this study. We lhank H.A.Kretzschmar (Gottingen) and M.Volpd (Krefeld) for preparing and providing tissues, Wolfgang Engel (Gottingen) and J5rg T.Epplen (Bochum) for valuable discussions, Friedmar Kreuz (Gottingen) for his support in examining clinical data, Sflke Wagner (Gottingen) and Susanne Potisek (Bochum) for excellent technical assistance, I.Flamme (Bochum) for dissection of tissues, P.Numberg (Berlin) for numerous DNA samples and Derek Murphy (Gottingen) for reading the manuscript. This work was supported by grants of the Wilhelm Sander Stiftung, Neustadt a.d. Donau (U.T., No 91.016.1) and the DFG (Ri 682, 1-1).

Research Areas and Centers

Research Area: Medical Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/hmg/2.12.2063

Cite this

@article{9ad3217db15640739bf994ff4d08cebb,

title = "Mitotic stability and meiotic variability of the (CAG)n repeat in the huntington disease gene",

abstract = "The gene causing Huntingtons's disease, an autosomal dominantly Inherited, neurodegenerative disorder, has been Identified recently. The corresponding mutation Is Involving an expansion In the number of (CAG)n repeats In the coding region of the Huntington's disease gene on chromosome 4. In this report, we demonstrate the length variation of the repeat In 513 non-HD chromosomes from normal Individuals and HD patlents showing 23 alleles with 11 to 33 repeats. Analyzing the Inherltance of the (CAG)n stretch we found melotic instability for HD alleles ([CAG]40 to [CAG]75) with a mutation frequency of approximately 0.7, while In 431 meloses of normal alleles only two expanslons were Identified. The risk of expansion during spermatogenesis is enhanced compared to oogenesls explaining juvenile onset by transmission from affected fathers. Further, the number of (CAG)n copies In an affected individual In relation to the sex of the transmitting parent was evaluated and no significant differences were found. No mosalcism or differences In the repeat lengths were observed In the DNA from different tissues Including brain and lymphocytes of two HD patients indicating mltotic stability of the mutation. Therefore, the determination of the repeat number In the DNA of blood lymphocytes Is probably representative of all tissues In a patient.",

author = "Christine Z{\"u}hlke and Olaf Riess and Barbara Bockel and Herwlg Lange and Ulrike Thies",

note = "Funding Information: We would li e to thank the patients, their families and clinicians, whose cooperation was essential in this study. We lhank H.A.Kretzschmar (Gottingen) and M.Volpd (Krefeld) for preparing and providing tissues, Wolfgang Engel (Gottingen) and J5rg T.Epplen (Bochum) for valuable discussions, Friedmar Kreuz (Gottingen) for his support in examining clinical data, Sflke Wagner (Gottingen) and Susanne Potisek (Bochum) for excellent technical assistance, I.Flamme (Bochum) for dissection of tissues, P.Numberg (Berlin) for numerous DNA samples and Derek Murphy (Gottingen) for reading the manuscript. This work was supported by grants of the Wilhelm Sander Stiftung, Neustadt a.d. Donau (U.T., No 91.016.1) and the DFG (Ri 682, 1-1).",

year = "1993",

month = dec,

doi = "10.1093/hmg/2.12.2063",

language = "English",

volume = "2",

pages = "2063--2067",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "12",

}

TY - JOUR

T1 - Mitotic stability and meiotic variability of the (CAG)n repeat in the huntington disease gene

AU - Zühlke, Christine

AU - Riess, Olaf

AU - Bockel, Barbara

AU - Lange, Herwlg

AU - Thies, Ulrike

N1 - Funding Information: We would li e to thank the patients, their families and clinicians, whose cooperation was essential in this study. We lhank H.A.Kretzschmar (Gottingen) and M.Volpd (Krefeld) for preparing and providing tissues, Wolfgang Engel (Gottingen) and J5rg T.Epplen (Bochum) for valuable discussions, Friedmar Kreuz (Gottingen) for his support in examining clinical data, Sflke Wagner (Gottingen) and Susanne Potisek (Bochum) for excellent technical assistance, I.Flamme (Bochum) for dissection of tissues, P.Numberg (Berlin) for numerous DNA samples and Derek Murphy (Gottingen) for reading the manuscript. This work was supported by grants of the Wilhelm Sander Stiftung, Neustadt a.d. Donau (U.T., No 91.016.1) and the DFG (Ri 682, 1-1).

PY - 1993/12

Y1 - 1993/12

N2 - The gene causing Huntingtons's disease, an autosomal dominantly Inherited, neurodegenerative disorder, has been Identified recently. The corresponding mutation Is Involving an expansion In the number of (CAG)n repeats In the coding region of the Huntington's disease gene on chromosome 4. In this report, we demonstrate the length variation of the repeat In 513 non-HD chromosomes from normal Individuals and HD patlents showing 23 alleles with 11 to 33 repeats. Analyzing the Inherltance of the (CAG)n stretch we found melotic instability for HD alleles ([CAG]40 to [CAG]75) with a mutation frequency of approximately 0.7, while In 431 meloses of normal alleles only two expanslons were Identified. The risk of expansion during spermatogenesis is enhanced compared to oogenesls explaining juvenile onset by transmission from affected fathers. Further, the number of (CAG)n copies In an affected individual In relation to the sex of the transmitting parent was evaluated and no significant differences were found. No mosalcism or differences In the repeat lengths were observed In the DNA from different tissues Including brain and lymphocytes of two HD patients indicating mltotic stability of the mutation. Therefore, the determination of the repeat number In the DNA of blood lymphocytes Is probably representative of all tissues In a patient.

AB - The gene causing Huntingtons's disease, an autosomal dominantly Inherited, neurodegenerative disorder, has been Identified recently. The corresponding mutation Is Involving an expansion In the number of (CAG)n repeats In the coding region of the Huntington's disease gene on chromosome 4. In this report, we demonstrate the length variation of the repeat In 513 non-HD chromosomes from normal Individuals and HD patlents showing 23 alleles with 11 to 33 repeats. Analyzing the Inherltance of the (CAG)n stretch we found melotic instability for HD alleles ([CAG]40 to [CAG]75) with a mutation frequency of approximately 0.7, while In 431 meloses of normal alleles only two expanslons were Identified. The risk of expansion during spermatogenesis is enhanced compared to oogenesls explaining juvenile onset by transmission from affected fathers. Further, the number of (CAG)n copies In an affected individual In relation to the sex of the transmitting parent was evaluated and no significant differences were found. No mosalcism or differences In the repeat lengths were observed In the DNA from different tissues Including brain and lymphocytes of two HD patients indicating mltotic stability of the mutation. Therefore, the determination of the repeat number In the DNA of blood lymphocytes Is probably representative of all tissues In a patient.

UR - https://www.scopus.com/pages/publications/0027745692

U2 - 10.1093/hmg/2.12.2063

DO - 10.1093/hmg/2.12.2063

M3 - Journal articles

C2 - 8111374

AN - SCOPUS:0027745692

SN - 0964-6906

VL - 2

SP - 2063

EP - 2067

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 12

ER -