A genetic cluster of patients with variant xeroderma pigmentosum with two different founder mutations.
BACKGROUND
Xeroderma pigmentosum (XP) is a rare human syndrome associated with hypersensitivity to sunlight and a high frequency of skin tumours at an early age. We identified a community in the state of Goias (central Brazil), a sunny and tropical region, with a high incidence of XP (17 patients among approximately 1000 inhabitants).


OBJECTIVE
To identify gene mutations in the affected community and map the distribution of the affected alleles, correlating the mutations with clinical phenotypes.


METHODS
Functional analyses of DNA repair capacity and cell-cycle responses after ultraviolet exposure were investigated in cells from local patients with XP, allowing the identification of the mutated gene, which was then sequenced to locate the mutations. A specific assay was designed for mapping the distribution of these mutations in the community.


RESULTS
Skin primary fibroblasts showed normal DNA damage removal but abnormal DNA synthesis after ultraviolet irradiation and deficient expression of the Polη protein, which is encoded by POLH. We detected two different POLH mutations: one at the splice donor site of intron 6 (c.764 +1 G>A), and the other in exon 8 (c.907 C>T, p.Arg303X). The mutation at intron 6 is novel, whereas the mutation at exon 8 has been previously described in Europe. Thus, these mutations were likely brought to the community long ago, suggesting two founder effects for this rare disease.


CONCLUSIONS
This work describes a genetic cluster involving POLH, and, particularly unexpected, with two independent founder mutations, including one that likely originated in Europe.
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
V
V
Munford
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
L P
LP
Castro
Secretariat of Health, Goiania, GO, Brazil.
R
R
Souto
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
L K
LK
Lerner
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
J B
JB
Vilar
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
C
C
Quayle
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
H
H
Asif
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.|Department of Biochemistry and Molecular Biology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
A P
AP
Schuch
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
T A
TA
de Souza
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
S
S
Ienne
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
F I A
FIA
Alves
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
L M S
LMS
Moura
Molecular Oncology Center, Hospital Sírio-Libanês, São Paulo, SP, Brazil.
P A F
PAF
Galante
Molecular Oncology Center, Hospital Sírio-Libanês, São Paulo, SP, Brazil.
A A
AA
Camargo
Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
R
R
Liboredo
Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
S D J
SDJ
Pena
UMR 8200 CNRS, Institut Gustave Roussy and University Paris-Saclay, Villejuif, France.
A
A
Sarasin
General Hospital of Goiania, Goiania, GO, Brazil.
S C
SC
Chaibub
Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
C F M
CFM
Menck
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001938:Brazil / Q000208:ethnology; D005060:Europe / Q000208:ethnology; D005260:Female; D018703:Founder Effect; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D012878:Skin Neoplasms / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014983:Xeroderma Pigmentosum / Q000208:ethnology / Q000235:genetics*