Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene.
Heterozygous mutations in the telomerase components TERT, the reverse transcriptase, and TERC, the RNA template, cause autosomal dominant dyskeratosis congenita due to telomere shortening. Anticipation, whereby the disease severity increases in succeeding generations due to inheritance of shorter telomeres, is a feature of this condition. Here we describe 2 families in which 2 TERT mutations are segregating. Both families contain compound heterozygotes. In one case the proband is homozygous for a novel mutation causing a P704S substitution, while his father's second allele encodes an H412Y mutation. The proband in the second family has mutant alleles Y846C and H876Q. Transfection studies show codominant expression of the mutated alleles with no evidence of a dominant negative effect or of intragenic complementation. Thus in these families the expression of both TERT alleles and the inherited telomere length contribute to the clinical phenotype.
Du
Hong-Yan
HY
Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Pumbo
Elena
E
Manley
Peter
P
Field
Joshua J
JJ
Bayliss
Susan J
SJ
Wilson
David B
DB
Mason
Philip J
PJ
Bessler
Monica
M
D000328:Adult; D000369:Aged, 80 and over; D002648:Child; D019871:Dyskeratosis Congenita / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism
C509186:TERT protein, human; D019098:Telomerase