Jm. Graham et al., Cerebro-oculo-facio-skeletal syndrome with a nucleotide excision-repair defect and a mutated XPD gene, with prenatal diagnosis in a triplet pregnancy, AM J HU GEN, 69(2), 2001, pp. 291-300
Citations number
34
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Molecular Biology & Genetics
Cerebro-oculo-facio-skeletal (COFS) syndrome is a recessively inherited rap
idly progressive neurologic disorder leading to brain atrophy, with calcifi
cations, cataracts, microcornea, optic atrophy, progressive joint contractu
res, and growth failure. Cockayne syndrome (CS) is a recessively inherited
neurodegenerative disorder characterized by low to normal birth weight, gro
wth failure, brain dysmyelination with calcium deposits, cutaneous photosen
sitivity, pigmentary retinopathy and/or cataracts, and sensorineural hearin
g loss. Cultured CS cells are hypersensitive to UV radiation, because of im
paired nucleotide-excision repair (NER) of UV-induced damage in actively tr
anscribed DNA, whereas global genome NER is unaffected. The abnormalities i
n CS are caused by mutated CSA or CSB genes. Another class of patients with
CS symptoms have mutations in the XPB, XPD, or XPG genes, which result in
UV hypersensitivity as well as defective global NER; such patients may conc
urrently have clinical features of another NER syndrome, xeroderma pigmento
sum (XP). Clinically observed similarities between COFS syndrome and CS hav
e been followed by discoveries of cases of COFS syndrome that are associate
d with mutations in the XPG and CSB genes. Here we report the first involve
ment of the XPD gene in a new case of UV-sensitive COFS syndrome, with hete
rozygous substitutions-a R616W null mutation (previously seen in patients i
n XP complementation group D) and a unique D681N mutation-demonstrating tha
t a third gene can be involved in COFS syndrome. We propose that COFS syndr
ome be included within the already known spectrum of NER disorders: XP, CS,
and trichothiodystrophy. We predict that future patients with COFS syndrom
e will be found to have mutations in the CSA or XPB genes, and we document
successful use of DNA repair for prenatal diagnosis in triplet and singleto
n pregnancies at risk for COFS syndrome. This result strongly underlines th
e need for screening of patients with COFS syndrome, for either UV sensitiv
ity or DNA-repair abnormalities.