Giovanni Stevanin

A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease–like 2

We recently described a disorder termed Huntington disease–like 2 (HDL2) that completely segregates with an unidentified CAG/CTG expansion in a large pedigree (W). We now report the cloning of this expansion and its localization to a variably spliced exon of JPH3 (encoding junctophilin-3), a gene involved in the formation of junctional membrane structures.

Chapter 4 Clinical and Genetic Aspects of Spinocerebellar Ataxias with Emphasis on Polyglutamine Expansions

Publisher Summary This chapter discusses the clinical and genetical aspects of spinocerebellar ataxias with emphasis on polyglutamine expansions. Autosomal dominant cerebellar ataxias (ADCAs), alternatively called spinocerebellar ataxias (SCAs), are a highly heterogeneous group of neurodegenerative disorders characterized by cerebellar ataxia variably associated with other neurological signs. Seven of these disorders are often referred to as polyglutamine diseases caused by translated CAG repeat expansions. Clinically, these disorders are characterized by a wide range of phenotypes depending on the responsible locus, the size of the expansion, and disease duration. These disorders manifest above a threshold of CAG repeats that varies according to the gene. When large and not interrupted, the CAG repeats are unstable upon transmission, mostly resulting in expansions particularly during paternal transmissions. This observation and the strong negative correlation between the size of the expansion and the age at onset account for the phenomenon of anticipation often observed in families. The relative frequency of the responsible genes varies according to geographical origin, and polyglutamine diseases account for 40–80% of ADCAs. Genetic diagnosis, now possible in several of these disorders, does not yet permit specific treatment but allows accurate genetic counseling and offers the possibility of presymptomatic and prenatal testing.