Cystic fibrosis - defect in chloride ion transport, leads to gastro-intestinal insufficiency
Wilson disease - copper accumulation in the liver and brain. Leads to liver failure, dystonia, dementia, haemolytic anaemia, reduced renal function, jaundice
Bloom syndrome - genomic instability in somatic cells, leads to telangiectatic facial erythema, photosensivity, dwarfism and other abnormalities
Werner's syndrome - DNA helicase Q-related protein; premature ageing and strong predisposition to cancer
X-linked adrenoleukodystrophy - accumulation of very-long-chain fatty acids, leads to demyelination of the central nervous system and death, or in a milder form to adrenal insufficiency
Ataxia telangiectasia - cerebellar degeneration and mental retardation, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity
Fanconi syndrome - nephrolithiasis: renal deficiency
Amyotrophic lateral sclerosis - decreased removal of superoxide radicals, leads to a progressive loss of motor function
Myotonic dystrophy - myotonia, muscular dystrophy, cataracts
Lowe syndrome - deficient inositol phosphate metabolism, leads to mental retardation, renal abnormalities, cataracts and glaucoma
Neurofibromatosis (type 1) - fibromatous skin tumors, skin marks
Migraine - calcium channel; familial hémiplégie migraine and episodic ataxia
Batten's disease - CLN3 gene product may function as a chaperone involved in the folding/unfolding or assembly/disassembly of other proteins, specifically subunit c of the ATP synthase complex organisms will provide 'reliable functional annotation of the human DNA sequence' (Chervitz et al., 1998). As befits a relatively young and visible field, the Internet plays a central role in cross-referencing and homology searching of genome sequences via a publicly accessible database (see Bassett et al., 1997; Foury, 1997; Chervitz et al., 1998).
The homology of yeast sequences with those implicated in human heritable diseases provides, if it was needed, the primary justification for the yeast genome project. Remarkably, this single celled 'primitive' eukaryote provides an experimental vehicle for probing the genetics and biochemistry of human diseases with the ultimate goal of control or avoidance. Comparative genomics provides the experimental scenarios that are already enabling yeast to be used as a screen for antitumour and antiviral drugs. The construction of the 'minimalist yeast' described above is anticipated to be an important next step in such a programme (Oliver, 1996).
The power of comparative genomics has been brought to life from work on Werner's syndrome and Batten's disease (Table 4.15) in yeast. The former results in premature ageing (see Section 184.108.40.206), whereas Batten's disease is an inherited neurodegenerative disease in children with an incidence of 1 in 12 500 live births in the USA (Pearce & Sherman, 1998). Batten's disease is characterised by a decline in mental abilities, untreatable seizures, blindness, loss of motor skills and premature death. Comparative genomics have shown that, in yeast, the product of the nonessential BTN1 gene is 39% identical and 59% similar to the protein from the human gene (CLN3) for Batten's disease. Compelling work from Pearce and co-workers has shown that yeast is an excellent experimental model to determine the function of the CLN3 gene. The human protein can be expressed in yeast and complements functions lost by deletion of the BTN1 gene (Pearce & Sherman, 1998). Subsequent work (Pearce et al., 1999) has suggested that Batten's disease is caused by a defect in vacuolar pH control. Tellingly, the authors conclude that their work 'draws parallels between fundamental biological processes in yeast and previously observed characteristics of neurodegeneration in humans' (Pearce et al., 1999).
Coincidentally, yeast may also throw some light on another, more high-profile neurodegenerative disease, Creutzfeldt-Jakob disease, that has been associated with BSE (bovine spongiform encephalopathy) or 'mad cow disease' in cattle. Intriguingly these disorders are believed to be brought about by infectious proteins or 'prions' transmitted via a 'protein only' mechanism which is not coded for genetically. It is thought that the protein - which is encoded in the usual manner but is free of DNA or RNA - flips its shape to form an abnormal insoluble protein (prion) which, consequently, loses its normal function. The prion is infectious and multiplies by converting other copies of the normal protein into prions by inducing the benign molecules to change shape (see Fig. 4.18). Accordingly, Wickner et al. (1999) have described prions as 'genes composed of altered proteins rather than nucleic acids'. Given this challenging notion it is not surprising that the maverick protein concept remains controversial. However the originator of the prion concept, Stanley Pruisner, - was awarded the Nobel Prize in 1997 (see review by Pruisner, 1995).
Inevitably, given its increasing use in probing human disease, work with S. cere-visiae (Wickner, 1997) is making a substantial contribution to unravelling the mammalian prion hypothesis. However, this is an increasingly complex and per-
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