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...

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Bibliographic Details
Published in:	Journal of investigative dermatology Vol. 118; no. 6; pp. 972 - 982
Main Authors:	EMMERT, Steffen, SLOR, Hanoch, LEE, Myung-Moo, CROLLICK, Jill, INUI, Hiroki, UEDA, Takahiro, HEDAYATI, Mohammad, GROSSMAN, Lawrence, SHAHLAVI, Tala, CLEAVER, James E, KRAEMER, Kenneth H, BUSCH, David B, BAKTO, Sima, ALBERT, Roberta B, COLEMAN, Donna, KHAN, Sikandar G, ABU-LIBDEH, Bassam, DIGIOVANNA, John J, CUNNINGHAM, Bari B
Format:	Journal Article
Language:	English
Published:	Danvers, MA Nature Publishing 01-06-2002
Subjects:	Adolescent Adult Biological and medical sciences Cell Line, Transformed Cell Survival - radiation effects Child, Preschool Cockayne Syndrome - genetics Cockayne Syndrome - pathology Dermatology DNA Repair DNA-Binding Proteins - genetics Endonucleases Female Fibroblasts - cytology Genotype Hereditary diseases of the skin. Congenital diseases of the skin. Haemangioma of the skin, of mucosae and of soft tissue Humans Infant Medical sciences Mutation, Missense Nervous System Malformations - genetics Nervous System Malformations - pathology Nuclear Proteins Pedigree Pigmentary diseases of the skin Polymorphism, Restriction Fragment Length RNA - biosynthesis RNA, Messenger - analysis Transcription Factors Ultraviolet Rays Xeroderma Pigmentosum - genetics Xeroderma Pigmentosum - pathology Human Photosensitivity Skin disease Nervous system diseases Pigmentation disorder Etiopathogenesis Xeroderma pigmentosum Genotype Infant Developmental disorder Experimental study Genetic disease Case study Photodermatosis Relation Cell line Female Neurological disorder
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Summary:	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.
Bibliography:	ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3
ISSN:	0022-202X 1523-1747
DOI:	10.1046/j.1523-1747.2002.01782.x