Human Molecular Genetics, Vol 6, 2265-2269, Copyright © 1997 by Oxford University Press
JR Yates, I van Bakel, T Sepp, SJ Payne, DW Webb, NC Nevin and AJ Green
We have investigated a family in which three siblings with the autosomal
dominant disorder tuberous sclerosis had unaffected parents. The family
were typed for polymorphic markers spanning the two genes known to cause
tuberous sclerosis located at 9q34 (TSC1) and 16p13.3 (TSC2). TSC1 markers
showed different maternal and paternal haplotypes in affected children,
excluding a mutation in TSC1 as the cause of the disease. For the TSC2
markers all the affected children had the same maternal and paternal
haplotypes, as did three of their unaffected siblings. Mutation screening
by RT-PCR and direct sequencing of the TSC2 gene identified a 4 bp
insertion TACT following nucleotide 2077 in exon 18 which was present in
the three affected children but not in five unaffected siblings or the
parents. This mutation would cause a frameshift and premature termination
at codon 703. Absence of the mutation in lymphocyte DNA from the parents
was consistent with germline mosaicism and this was confirmed by our
finding of identical chromosome 16 haplotypes in affected and unaffected
siblings, providing unequivocal evidence of two different cell lines in the
gametes. Molecular analysis of the TSC2 alleles present in the affected
subjects showed that the mutation had been inherited from the mother. This
is the first case of germline mosaicism in tuberous sclerosis proven by
molecular genetic analysis and also the first example of female germline
mosaicism for a characterized autosomal dominant gene mutation apparently
not associated with somatic mosaicism.
ARTICLES
Female germline mosaicism in tuberous sclerosis confirmed by molecular genetic analysis
Department of Pathology, University of Cambridge, Box 134 Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. jyates@hgmp.mrc.ac.uk
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