Mutations in theC7orf11(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.

TTDN1 is a Plk1-interacting protein involved in maintenance of cell cycle integrity

“…Previous reports indicated that TTDN1 was mutated in patients with Amish brittle hair syndrome (ABSH) and in other non-photosensitive TTD cases with mental retardation and decreased fertility [25,37]. However, the physiological functions of TTDN1 were unknown.…”

TTDA: Big impact of a small protein

“…Nothing is currently known about the function of C7orf11/TTDN1, i.e. the gene mutated in a small proportion of non-photosensitive TTD cases that show normal response to UV-light and TFIIH steady state level [13,14]. To investigate which genes are mutated within the non-photosensitive form of TTD could lead to relevant information on the origin of the pathological TTD features in general.…”

“…Mutations in the TTDN1 gene are associated with the nonphotosensitive form of TTD [13,14]. However, the majority of non-photosensitive TTD patients (approximately 80%) has not yet been linked with any causative gene.…”

Genotype-phenotype relationships in trichothiodystrophy patients with novel splicing mutations in theXPDgene

“…Allele-specific assays were carried out together with a control primer pair for the GAPDH gene [Botta et al, 2007] by quantification of allele-specific RT-PCR products as well as by real-time allele-specific RT-PCR. PCR reactions were set up in 20 ml using GeneSpin reagents (GeneSpin, Milano, Italy).…”