FRAXF and FAM11A

The FRAXF repeat expansion is rare, but has not been surveyed in detail. Individuals with expansions were identified in cytogenetic fragile site studies among patients with MR prior to molecular testing for FRAXA and FRAXE. Since such studies are much less frequent now, and since the phenotype caused by FRAXF expansion (if any) does not appear to encompass cognitive disabilities, no surveys for FRAXF expansions have been carried out. In the general population, the repeat is found to be composed...

Mouse Model of Fmr2 Deficiency and Drosophila Lilli

Gu et al. (2002) reported a mouse model for Fmr2 deficiency where the gene had been disrupted in the first exon with an expression cassette that allowed the E. coli lacZ gene to be expressed under control of the Fmr2 promoter. This provided the ability to follow expression of the gene through staining for beta-galactosidase activity, and was used to define the expression pattern of Fmr2 in early embryos. Fmr2 is expressed in neurons early in development expression can be seen as early as 10.5...

Loss of Cystatin B Function and Disease Pathophysiology

As discussed already, despite the different types of EPM1 mutations, they all have as a consequence the loss of cystatin B function through three apparent mechanisms lack of the protein, abnormal localization, and deletion of critical residues. Consistently, lymphoblastoid lines from EPM1 patients show enhanced activity of those proteinases that are normally inhibited by cys-tatin B cathepsins B, L, and S (Kinne et al. 2002). A mouse model of EPM1 with a deletion of the cystatin B gene was...

Clinical features of FRAXE disease

Patients with the expanded FRAXE repeats show mild to borderline mental retardation, with delays in language development a common problem. Some FRAXE patients also exhibit behavioral abnormalities, such as attention deficit, hyperactivity, autistic-like behavior, even schizophrenia and obsessive-compulsive disorder (OCD) (Gecz 2000b Wang et al. 2003). Most patients with FRAXE are not easily distinguished from the general population as there are no consistent physical features in these patients,...

References

Abel A, Walcott J, Woods J, Duda J, Merry DE (2001) Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. Hum Mol Genet 10 107-116 Adachi H, Katsuno M, Minamiyama M, Sang C, Pagoulatos G, Angelidis C, Kusakabe M, Yoshiki A, Kobayashi Y, Doyu M, Sobue G (2003) Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor...

Consequences of Repeat Expansion

As can be gathered from chapters in this volume, research is beginning to clarify the relationship between nucleotide expansions and their consequences. Perhaps not surprisingly, these consequences depend on some combination of the properties of the repeat itself, its location in the affected gene, and the function of that gene. When the repeat is located in an open reading frame, the relationship between expansion and disease pathology is superficially quite straightforward nucleotide...

RNA Gain of Function

A RNA gain of function has been proposed as a pathogenic mechanism for several neurodegenerative disorders caused by repeat expansions (Liquori et al. 2001 Mankodi et al. 2002 Miller et al. 2000 Ranum and Day 2004 Savkur et al. 2001 Taneja et al. 1995 Timchenko et al. 1996, also reviewed in this volume). In myotonic dystrophy type 1 (DM1), a large d(CTG) repeat expansion in the 3' untranslated region (UTR) of the DMPK gene results in a transcript containing expanded r(CUG) repeats. The r(CUG)...

Other Extracerebellar Signs and Symptoms

Some SCA10 patients of Mexican origin have additional phenotypes beyond cerebellar degeneration and epileptic seizures (Grewal et al. 1998, 2002 Lin and Ashizawa 2003 Matsuura et al. 1999, 2000 Rasmussen et al. 2001). More extra-cerebellar signs and non-neuronal involvement have been observed in some families. Variable degrees of pyramidal signs, including hyperreflexia, leg spasticity and Babinski's sign, were reported. Affected individuals often complain of mild sensory loss in distal lower...

PolyQ Diseases as Transcriptionopathies

Polyq Disease

When localized in the nucleus, polyQ-expanded proteins aberrantly interact with a variety of transcription factors, many of which contain a polyQ or glutamine-rich domain Table 2 . Certain transcription pathways, namely those involving the cyclic AMP response element CRE -binding protein CREB and specificity protein-1 Sp1 have been implicated in the pathogenesis of multiple polyQ diseases. Interestingly, the cofactor TBP-associated factor 4 TAF4 formerly TAFII130 , which was independently...