DMD Trp3X nonsense mutation associated with a founder effect in North American families with mild Becker muscular dystrophy.
A recurrent exon 1 nonsense mutation in the DMD gene, p.Trp3X (c.9G>A), was first ascertained in a proband with no symptoms until age 20 and who walked until the age of 62. Six other unrelated kindreds carrying a p.Trp3X mutation were subsequently ascertained, five from North America and one from Italy. In six of the seven kindreds, the proband presented in childhood incidental to elevated creatine kinase levels detected in the context of other illnesses, or in the setting of cramps with or without rhabdomyolysis. Genetic analysis by high density SNP genotyping demonstrates that the six North American families share a 3.7 Mbp haplotype surrounding the p.Trp3X allele, signifying that this is a founder mutation in these individuals. The size of the founder haplotype and the structure of shared genome-wide segments suggests that the minimal age of this mutation is >6 generations. The discovery of the first DMD founder mutation, associated with a mild Becker phenotype, suggests that the prevalence of hypomorphic dystrophin mutations should be re-examined with the use of improved genomic analysis.
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, United States of America.
Kevin M
KM
Flanigan
Diane M
DM
Dunn
Andrew
A
von Niederhausern
Michael T
MT
Howard
Jerry
J
Mendell
Anne
A
Connolly
Carol
C
Saunders
Ann
A
Modrcin
Majed
M
Dasouki
Giacomo P
GP
Comi
Roberto
R
Del Bo
Angela
A
Pickart
Richard
R
Jacobson
Richard
R
Finkel
Livija
L
Medne
Robert B
RB
Weiss
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X; D018389:Codon, Nonsense / Q000235:genetics*; D016189:Dystrophin / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D018703:Founder Effect; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics*; D009656:North America; D014364:Tryptophan / Q000235:genetics*; D055815:Young Adult
D018389:Codon, Nonsense; C484258:DMD protein, human; D016189:Dystrophin; D014364:Tryptophan