Trichothiodystrophy

While defects in protein XPD often cause typical XP symptoms, some defects in the same protein lead to trichothiodystrophy (TTD, brittle hair disease). The hair is sulfur deficient, and scaly skin (ichthyosis, Box 8-F), mental retardation, and other symptoms are observed.0 Like their yeast counterparts (proteins RAD3 and RAD25), XPB and XPD are both DNA helicases.0 They also constitute distinct subunits of the human transcription factor TFIIHP, which is discussed in Chapter 28. It seems likely that XPD is involved in transcription-coupled repair (TCR) of DNA.° °i-s This is a subpathway of the nucleotide excision repair (NER) pathway, which allows for rapid repair of the transcribed strand of DNA. This is important in tissues such as skin, where the global NER process may be too slow to keep up with the need for rapid protein synthesis. Transcription-coupled repair also appears to depend upon proteins CSA and CSB, defects which may result in the rare cockayne syndrome.13 0 4 11 Patients are not only photosensitive but have severe mental and physical retardation including skeletal defects and a wizened appearance. 

Trichothiodystrophy (TTD) is a disease that is characterized by sulfur-deficient brittle hair, ichthyosis (fish-like scales on the skin), mental retardation, and grown... 

Photosensitive trichothiodystrophy (TTD) patients have defects in the XPD or XPB gene and cannot repair cyclobutane dimers (CPD). The phenotype is characterized by many of the symptoms common to the CS patients but with the additional characteristics of brittle hair and nails, and scaly skin. Why mutations in XPD and XPB can give rise to both XP and TTD is explained by the dual functions of the proteins in NER and transcription. The special hallmarks of TTD are thus due to reduced transcription and expression of matrix proteins [76]. 

Bootsma, D Kraemer, K.H., Cleaver, J.E., and Hoeijmakers, J.H.J. (1998) Nucleotide excision repair syndromes xeroderma pigmentosum, cockayne syndrome, and trichothiodystrophy, in The Genetic Basis of Cancer (eds B. Vogelstein and K.W. Kinzler), McGraw-Hill, New York, pp. 245-274. 

Lehmann, A.R. (2003) DNA repair -deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Biochimie, 85, 1101-1111. 

Kraemer, K.H., Patronas, N.J., Schiffmann, R., Brooks, B.P., Tamura, D., and DiGiovanna, J.J. (2007) Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome a complex genotype-phenotype relationship. Neuroscience, 145,1388-1396. 

Trichothiodystrophy is a number of syndromes affecting both the hair and the nails resulting from mutations. The hair in this disease is thin or even sparse and brittle. Gillespie and Marshall [136] indicate that in this disease the hair contains only about one-half the cystine content of normal hair producing the brittleness of this condition. 

Monilethrix is a genetic anomaly in which hair fibers contain periodic constrictions along the fiber axis. Monilethrix hairs tend to fracture at these constrictions [63] and therefore must exhibit abnormal stretching behavior. Trichorrhexis nodosa is another abnormal condition, where hair fibers contain nodes at irregular intervals along the fiber axis. These nodes actually contain tiny fractures and tend to form broom like breaks [63] under stress. Therefore, nodosa hair fibers should also exhibit abnormal stretching behavior. Other hair shaft anomalies such as trichothiodystrophy and Menkes syndrome should also display abnormal stretching behavior consistent with the abnormal hair shaft condition associated with these diseases. 

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