Relationship of neurologic degeneration to genotype in three xeroderma pigmentosum group G patients.
We studied three newly diagnosed xeroderma pigmentosum complementation group G patients with markedly different clinical features. An Israeli-Palestinian girl (XP96TA) had severe abnormalities suggestive of the xeroderma pigmentosum/Cockayne syndrome complex including sun sensitivity, neurologic and developmental impairment, and death by age 6 y. A Caucasian girl (XP82DC) also had severe sun sensitivity with neurologic and developmental impairment and died at 5.8 y. In contrast, a mildly affected 14-y-old Caucasian female (XP65BE) had sun sensitivity but no neurologic abnormalities. XP96TA, XP82DC, and XP65BE fibroblasts showed marked reductions in post-ultraviolet cell survival and DNA repair but these were higher in XP65BE than in XP82DC. XP96TA fibroblasts had very low XPG mRNA expression levels whereas XP65BE fibroblasts had nearly normal levels. Host cell reactivation of an ultraviolet-treated reporter assigned all three fibroblast strains to the rare xeroderma pigmentosum complementation group G (only 10 other patients previously reported). XP96TA and XP82DC cells had mutations in both XPG alleles that are predicted to result in severely truncated proteins including stop codons and two base frameshifts. The mild XP65BE patient had an early stop codon mutation in the paternal allele. The XP65BE maternal allele had a single base missense mutation (G2817A, Ala874Thr) that showed residual ability to complement xeroderma pigmentosum complementation group G cells. These observations agree with earlier studies demonstrating that XPG mutations, which are predicted to lead to severely truncated proteins in both alleles, were associated with severe xeroderma pigmentosum/Cockayne syndrome neurologic symptoms. Retaining residual functional activity in one allele was associated with mild clinical features without neurologic abnormalities.
Emmert
Steffen
S
Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
Slor
Hanoch
H
Busch
David B
DB
Batko
Sima
S
Albert
Roberta B
RB
Coleman
Donna
D
Khan
Sikandar G
SG
Abu-Libdeh
Bassam
B
DiGiovanna
John J
JJ
Cunningham
Bari B
BB
Lee
Myung-Moo
MM
Crollick
Jill
J
Inui
Hiroki
H
Ueda
Takahiro
T
Hedayati
Mohammad
M
Grossman
Lawrence
L
Shahlavi
Tala
T
Cleaver
James E
JE
Kraemer
Kenneth H
KH
D000293:Adolescent; D000328:Adult; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000528:radiation effects; D002675:Child, Preschool; D003057:Cockayne Syndrome / Q000235:genetics / Q000473:pathology; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005838:Genotype; D006801:Humans; D007223:Infant; D020125:Mutation, Missense; D009421:Nervous System Malformations / Q000235:genetics* / Q000473:pathology*; D009687:Nuclear Proteins; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length; D012313:RNA / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics* / Q000473:pathology*; D000099250:DNA Excision Repair Protein ERCC-5
D004268:DNA-Binding Proteins; D004720:Endonucleases; D009687:Nuclear Proteins; D012313:RNA; D012333:RNA, Messenger; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5