The spectrum of KIAA0196 variants, and characterization of a murine knockout: implications for the mutational mechanism in hereditary spastic paraplegia type SPG8

Conclusions:
Our data do not support the current view that heterozygous loss of strumpellin/SHRC function leads to haploinsufficiency and, in turn, to HSP. The lethality of homozygous knockout mice, i.e. the effect of complete loss of function, also argues against a dominant negative effect of mutant on wild-type strumpellin in patients. Toxic gain-of-function represents a potential alternative explanation. Confirmation of this therapeutically relevant hypothesis in vivo, however, will require availability of appropriate knockin models.

Source: Orphanet Journal of Rare Diseases - November 16, 2015 Category: Internal Medicine Authors: Amir JahicMukhran KhundadzeNadine JaenischRebecca SchüleSven KlimpeStephan KlebeChristiane FrahmJan KassubekGiovanni StevaninLudger SchölsAlexis BriceChristian HübnerChristian Beetz Source Type: research