title: Constructive rescue of TFIIH instability by an alternative isoform of XPD derived from a mutated XPD allele in mild but not severe XP-D/CS.
abstract: Mutations in XPD cause xeroderma pigmentosum (XP), XP and Cockayne syndrome (CS) crossover syndrome (XP/CS), trichothiodystrophy and cerebro-oculo-facio-skeletal syndrome (COFS). COFS represents the most severe end of the CS spectrum. This study reports two Japanese patients, COFS-05-135 and COFS-Chiba1, who died at ages of <1 year and exhibited typical COFS manifestations caused by XPD mutations p.[I619del];[R666W] and p.[G47R];[I619del], respectively. Two other cases of severe XP-D/CS (XP group D/CS), XP1JI (p.[G47R];[0]) and XPCS1PV (p.[R666W];[0]), died at ages <2 years. On the other hand, two cases of mild XP-D/CS, XP1NE (p.[G47R];[L461V;V716_R730del]) and XPCS118LV (p.[L461V;V716_R730del];[R666W]), lived beyond 37 years of age. p.I619Del and p.[L461V;V716_R730del] are functionally null; therefore, despite the differences in clinical manifestations, the functional protein in all of these patients was either p.G47R or p.R666W. To resolve the discrepancies in these XPD genotype-phenotype relationships, the p.[L461V;V716_R730del] allele was analyzed and we found that p.[L461V;A717G] was expressed from the same allele as p.[L461V;V716_R730del] by authentic splicing. Additionally, p.[L461V;A717G] could partially rescue the loss of XPD function, resulting in the milder manifestations observed in XP1NE and XPCS118LV.
authors.affiliation: Human Cell Biology Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Horibata
authors.affiliation: Human Cell Biology Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kono
authors.affiliation: Human Cell Biology Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Ishigami
authors.affiliation: Human Cell Biology Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Neonatology, Chiba Children's Hospital, Midori-ku, Chiba, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Aizawa
authors.affiliation: Division of Neonatology, Chiba Children's Hospital, Midori-ku, Chiba, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kako
authors.affiliation: 1] Division of Clinical Genetics, Chiba Children's Hospital, Midori-ku, Chiba, Japan [2] Department of Pediatrics, Kawaguchi Kogyo General Hospital, Kawaguchi, Saitama, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Division of Medical Genetics, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
authors.forename: Rika
authors.initials: R
authors.lastname: Kosaki
authors.affiliation: Human Cell Biology Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Saijo
authors.affiliation: Human Cell Biology Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
authors.forename: Kiyoji
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D002460:Cell Line; D017809:Fatal Outcome; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D051758:Transcription Factor TFIIH / Q000235:genetics* / Q000378:metabolism; D014983:Xeroderma Pigmentosum / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D051758:Transcription Factor TFIIH; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human