𝔖 Bobbio Scriptorium
✦   LIBER   ✦

Genotype–phenotype relationships in trichothiodystrophy patients with novel splicing mutations in the XPD gene

✍ Scribed by Elena Botta; Tiziana Nardo; Donata Orioli; Roberta Guglielmino; Roberta Ricotti; Sergio Bondanza; Francesco Benedicenti; Giovanna Zambruno; Miria Stefanini

Publisher
John Wiley and Sons
Year
2008
Tongue
English
Weight
333 KB
Volume
30
Category
Article
ISSN
1059-7794

No coin nor oath required. For personal study only.

✦ Synopsis

Trichothiodystrophy (TTD) is a rare, autosomal recessive neurodevelopmental disorder most commonly caused by mutations in ERCC2 (XPD), a gene that encodes a subunit of the transcription/repair factor IIH (TFIIH). Here, we describe two TTD cases in which detailed biochemical and molecular investigations offered a clue to explain their moderately affected phenotype. Patient TTD22PV showed new mutated XPD alleles: one contains a nonsense mutation (c.1984C4T) encoding a nonfunctional truncated product (p.Gln662X) whereas the second carries a genomic deletion (c.2191-18_c.2213del) that affects the splicing of intron 22 and generates multiple out-of-frame transcripts from codon 731. XPD mRNA from the second allele corresponds to 20% of the total. The predicted proteins, which are longer than normal, affect the cellular repair activity but only partially interfere with TFIIH stability, suggesting that the observed changes in the C-ter region of XPD cause minor structural changes that do not drastically compromise the transcriptional activity of TFIIH. Patient TTD24PV was compound heterozygous for a typical TTD allele (c.2164C4T, p.Arg722Trp) and for a new XPD allele with a mutation that partially affects intron 10 splicing, resulting in both mutated and normal XPD transcripts (that together represent 15% of the total XPD mRNA). Compared to the previously described TTD compound heterozygotes for the Arg722Trp change, Patient TTD24PV's cells show similar level of TFIIH but increased repair activity, suggesting that even low amounts of normal XPD subunits are able to partially rescue the functionality of TFIIH complexes.

📜 SIMILAR VOLUMES

Mutations in the C7orf11 (TTDN1) gene in
Mutations in the C7orf11 (TTDN1) gene in six nonphotosensitive trichothiodystrophy patients: no obvious genotype–phenotype relationships
✍ Elena Botta; Judith Offman; Tiziana Nardo; Roberta Ricotti; Giovanna Zambruno; D 📂 Article 📅 2007 🏛 John Wiley and Sons 🌐 English ⚖ 192 KB

## Communicated by Arnold Munnich 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, photosen

Genotype-phenotype studies of six novel
Genotype-phenotype studies of six novel LPL mutations in Chinese patients with hypertriglyceridemia
✍ Lisa Y.S. Chan; Ching-Wan Lam; Ying-Tat Mak; Brian Tomlinson; Man-Woo Tsang; Lar 📂 Article 📅 2002 🏛 John Wiley and Sons 🌐 English ⚖ 178 KB

We screened 160 unrelated Chinese hypertriglyceridemic subjects for sequence alterations in the promoter and the 10 exons of the lipoprotein lipase (LPL) gene. We identified one reported mutation (L252R), one common polymorphism (S447X), and six novel mutations: V181I, C283Y, S298R and S338F (found

Identification of 16 novel mutations in
Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype–phenotype correlation in 38 classical citrullinemia patients
✍ Hong-Zhi Gao; Keiko Kobayashi; Ayako Tabata; Hideaki Tsuge; Mikio Iijima; Tomots 📂 Article 📅 2003 🏛 John Wiley and Sons 🌐 English ⚖ 195 KB

Classical citrullinemia (CTLN1), a rare autosomal recessive disorder, is caused by mutations of the argininosuccinate synthetase (ASS) gene, localized on chromosome 9q34.1. ASS functions as a rate-limiting enzyme in the urea cycle. Previously, we identified 32 mutations in the ASS gene of CTLN1 pati

A novel splice site mutation in the TRIM
A novel splice site mutation in the TRIM37 gene causes mulibrey nanism in a Turkish family with phenotypic heterogeneity
✍ P. Jagiello; C. Hammans; S. Wieczorek; L. Arning; A. Stefanski; H. Strehl; J.T. 📂 Article 📅 2003 🏛 John Wiley and Sons 🌐 English ⚖ 321 KB

Mulibrey nanism (muscle-liver-brain-eye nanism; MUL) is an autosomal recessively transmitted disease characterized by severe growth delays of prenatal onset caused by mutations in the TRIM37 gene. Recent studies on the subcellular localization revealed that the TRIM37 (KIAA0898) protein is located i