Trichothiodystrophy 3, Photosensitive

A number sign (#) is used with this entry because of evidence that photosensitive trichothiodystrophy-3 (TTD3) is caused by homozygous or compound heterozygous mutation in the TFB5 gene (GTF2H5; 608780), which encodes a subunit of the transcription/repair factor TFIIH, on chromosome 6q25.

Description

Trichothiodystrophy is a rare autosomal recessive disorder in which patients have brittle, sulfur-deficient hair that displays a diagnostic alternating light and dark banding pattern, called 'tiger tail banding,' under polarizing microscopy. TTD patients display a wide variety of clinical features, including cutaneous, neurologic, and growth abnormalities. Common additional clinical features are ichthyosis, intellectual/developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections. There are both photosensitive and nonphotosensitive forms of the disorder. Patients with TTD have not been reported to have a predisposition to cancer (summary by Faghri et al., 2008).

For a discussion of genetic heterogeneity of TTD, see 601675.

Clinical Features

Jorizzo et al. (1982) described a patient with typical symptoms of TTD: characteristic hair-shaft abnormalities with reduced sulfur content, collodion baby, short stature, ichthyosis, bilateral congenital cataracts, and asthmatic attacks. Stefanini et al. (1993) examined this patient at age 20 years and found that he had had recurrent infective exacerbations of his asthma and that he remained severely growth retarded (height and weight below the 3rd centile) and of limited intelligence (IQ 70-80). His ichthyosiform erythroderma continued. He had developed joint contractures of the hands due to the severe ichthyosiform involvement of the palms, but sensitivity to sunlight had been present from early childhood. There was, however, no significant freckling or other pigmentary changes, no telangiectases or actinic keratoses, and no skin tumors.

Biochemical Features

Stefanini et al. (1993) demonstrated that cells from the patient (TTD1BR) originally described by Jorizzo et al. (1982) were able to complement the excision-repair defect in all xeroderma pigmentosum (XP) complementation groups. They also showed that complementation was not intragenic. Thus, the cell strain represented a new excision-repair complementation group. Lehmann et al. (1994) recommended that this second complementation group be referred to as TTDA and its gene as TTDA.

Vermeulen et al. (2000) found that patients with the TTDA complementation form of trichothiodystrophy had a severely reduced steady-state level of the entire TFIIH complex. The reduction of TFIIH affected mainly its repair function and hardly influenced transcription. Petrini (2000) interpreted the findings as indicating that the normal TTDA protein modulates the proteasome-mediated degradation of TFIIH. Microinjected TFIIH is less stable in TTDA cells; the absence of TFIIH in TTDA cells would thus decrease its half-life and therefore its abundance. It is conceivable that a threshold level of TFIIH is required to switch between the transcriptional mode and the nucleotide excision repair (NER) mode. Below that threshold, the essential need for transcription functions would override the signal to switch to NER mode, and DNA repair would therefore be differentially affected.

Giglia-Mari et al. (2004) found that polynucleated fibroblasts from individuals with TTDA microinjected with GTF2H5 cDNA showed greater unscheduled DNA synthesis than uninjected neighboring cells. GTF2H5 cDNA corrected the repair defect of cells from individuals with TTDA to a level comparable to that observed in wildtype cells assayed in parallel, suggesting that the GTF2H5 gene is mutated in TTDA.

Molecular Genetics

In 3 unrelated individuals with TTDA, Giglia-Mari et al. (2004) identified different inactivating mutations in the GTF2H5 gene in homozygous or compound heterozygous state (see, e.g., R56X, 608780.0001 and L21P, 608780.0002). The severe effect of GTF2H5 mutations on NER function suggests that NER requires higher concentrations of TFIIH than does transcription. Live cell studies showed that TFIIH participates substantially longer in NER than in transcription (Hoogstraten et al., 2002), providing a possible explanation for the increased need for sufficient amounts of TFIIH in NER. Additionally, an altered structure of TFIIH caused by a mutant GTF2H5 may primarily affect NER function.