A prevalent mutation with founder effect in xeroderma pigmentosum group C from north Africa.
Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder that is associated with an inherited defect of the nucleotide excision repair pathway (NER). In this study, we investigated the involvement of XP genes in 86 XP patients belonging to 66 unrelated families, most of them consanguineous and originating from Maghreb. Sequencing analysis was performed either directly (44 probands) or after having previously characterized the involved XP gene by complementation assay (22 families). XPC and XPA mutations were respectively present in 56/66 and 8/66 probands. Strikingly, we identified the same homozygous frameshift mutation c.1643_1644delTG (p.Val548AlafsX25) in 87% of XP-C patients. Haplotype analysis showed a common founder effect for this mutation in the Mediterranean region, with an estimated age of 50 generations or 1,250 years. Among 7/8 XP-A patients, we found the previously reported nonsense homozygous XPA mutation (p.Arg228X). Six mutations--to our knowledge previously unreported--(five in XPC, one in XPA) were also identified. In conclusion, XPC appears to be the major disease-causing gene concerning xeroderma pigmentosum in North Africa. As the (p.Val548AlafsX25) XPC mutation is responsible for a huge proportion of XP cases, our data imply an obvious simplification of XP molecular diagnosis, at least in North Africa.
Soufir
Nadem
N
Laboratoire de Biochimie hormonale et génétique, Hôpital Bichat, APHP, Université Paris VII, 46 Rue Henri Huchard, Paris, France. nsoufir@yahoo.com
Ged
Cecile
C
Bourillon
Agnes
A
Austerlitz
Frederic
F
Chemin
Cécile
C
Stary
Anne
A
Armier
Jacques
J
Pham
Daniele
D
Khadir
Khadija
K
Roume
Joelle
J
Hadj-Rabia
Smail
S
Bouadjar
Bakar
B
Taieb
Alain
A
de Verneuil
Hubert
H
Benchiki
Hakima
H
Grandchamp
Bernard
B
Sarasin
Alain
A
D000293:Adolescent; D000328:Adult; D000352:Africa, Northern / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D014983:Xeroderma Pigmentosum / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics*; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics; D055815:Young Adult
D004268:DNA-Binding Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C086984:XPC protein, human