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PMID: 8128954 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Gonosomal mosaicism in myotonic dystrophy patients: involvement of mitotic events in (CTG)n repeat variation and selection against extreme expansion in sperm.

American journal of human genetics ·Vol. 54 ·No. 4 ·1994-04-00 ·Pages 575-85

Jansen G, Willems P, Coerwinkel M, Nillesen W, Smeets H, Vits L, Höweler C, Brunner H, Wieringa B

Abstract

Myotonic dystrophy (DM) is caused by abnormal expansion of a polymorphic (CTG)n repeat, located in the DM protein kinase gene. We determined the (CTG)n repeat lengths in a broad range of tissue DNAs from patients with mild, classical, or congenital manifestation of DM. Differences in the repeat length were seen in somatic tissues from single DM individuals and twins. Repeats appeared to expand to a similar extent in tissues originating from the same embryonal origin. In most male patients carrying intermediate- or small-sized expansions in blood, the repeat lengths covered a markedly wider range in sperm. In contrast, male patients with large allele expansions in blood (> 700 CTGs) had similar or smaller repeats in sperm, when detectable. Sperm alleles with > 1,000 CTGs were not seen. We conclude that DM patients can be considered gonosomal mosaics, i.e., combined somatic and germ-line tissue mosaics. Most remarkably, we observed multiple cases where the length distributions of intermediate- or small-sized alleles in fathers' sperm were significantly different from that in their offspring's blood. Our combined findings indicate that intergenerational length changes in the unstable CTG repeat are most likely to occur during early embryonic mitotic divisions in both somatic and germ-line tissue formation. Both the initial CTG length, the overall number of cell divisions involved in tissue formation, and perhaps a specific selection process in spermatogenesis may influence the dynamics of this process. A model explaining mitotic instability and sex-dependent segregation phenomena in DM manifestation is discussed.

MeSH Terms
Aged Alleles Blotting, Southern Codon DNA Mutational Analysis Female Gene Expression Regulation, Enzymologic Genetic Variation Genotype Germ-Line Mutation Humans Infant, Newborn Male Meiosis Mitosis Models, Genetic Mosaicism Myotonic Dystrophy/genetics Organ Specificity Pedigree Phenotype Polymerase Chain Reaction Protein Kinases/genetics Repetitive Sequences, Nucleic Acid Selection, Genetic Spermatozoa
Chemicals
Codon Protein Kinases
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Jansen G
Department of Cell Biology and Histology, Faculty of Medical Sciences, University of Nijmegen, The Netherlands.
Willems P
Coerwinkel M
Nillesen W
Smeets H
Vits L
Höweler C
Brunner H
Wieringa B
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
Published
1994-04-00
Pages
575-85
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1918095
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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