title: Mutations in the C7orf11 (TTDN1) gene in six nonphotosensitive trichothiodystrophy patients: no obvious genotype-phenotype relationships.
abstract: Trichothiodystrophy (TTD) is a rare autosomal recessive disorder whose defining feature is brittle hair. Associated clinical symptoms include physical and mental retardation of different severity, ichthyosis, premature aging, and, in half of the patients, photosensitivity. Recently, C7orf11 (TTDN1) was identified as the first disease gene for the nonphotosensitive form of TTD, being mutated in two unrelated cases and in an Amish kindred. We have evaluated the involvement of TTDN1 in 44 unrelated nonphotosensitive TTD cases of different geographic origin and with different disease severity. Mutations were found in six patients, five of whom are homozygous and one of whom is a compound heterozygote. All five identified mutations are deletions that have not been described before. Three are deletions of a few bases, resulting in frameshifts and premature termination codons. The other two include the whole TTDN1 gene, suggesting that TTDN1 is not essential for cell proliferation and viability. The severity of the clinical features does not correlate with the type of mutation, indicating that other factors besides TTDN1 mutations influence the severity of the disorder. Since only a small proportion of the analyzed cases were mutated in TTDN1, the nonphotosensitive form of TTD is genetically heterogeneous. Mutations in TTDN1 do not affect the response to ultraviolet (UV) light or the steady state level of the repair/transcription factor IIH (TFIIH), which is central to the onset of the photosensitive form of TTD.
authors.affiliation: Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche (CNR), Pavia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Botta
authors.forename: Judith
authors.initials: J
authors.lastname: Offman
authors.forename: Tiziana
authors.initials: T
authors.lastname: Nardo
authors.forename: Roberta
authors.initials: R
authors.lastname: Ricotti
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.forename: Daniela
authors.initials: D
authors.lastname: Sansone
authors.forename: Paolo
authors.initials: P
authors.lastname: Balestri
authors.forename: Anja
authors.initials: A
authors.lastname: Raams
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Kleijer
authors.forename: Nicolaas G J
authors.initials: NG
authors.lastname: Jaspers
authors.forename: Alain
authors.initials: A
authors.lastname: Sarasin
authors.forename: Alan R
authors.initials: AR
authors.lastname: Lehmann
authors.forename: Miria
authors.initials: M
authors.lastname: Stefanini
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured / Q000528:radiation effects; D002648:Child; D002675:Child, Preschool; D062465:Claudin-3; D004252:DNA Mutational Analysis; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006201:Hair Diseases / Q000235:genetics*; D006801:Humans; D007057:Ichthyosis / Q000235:genetics; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009260:Nail Diseases / Q000235:genetics; D010641:Phenotype; D051758:Transcription Factor TFIIH / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: C568122:CLDN3 protein, human; D062465:Claudin-3; D008565:Membrane Proteins; D051758:Transcription Factor TFIIH