July 2017 | Iúil 2017

Missense Mutation Causes Spinocerebellar Ataxia Type 29

Tue, 18 July 17 15:44

Researchers in UCD School of Medicine have recently published the genetic basis of a family’s presentation with ataxia in the Journal of Neurology.

They found a missense mutation in a gene known as ITPR1 which causes spinocerebellar ataxia type 29 (SCA29). Different mutations in this gene can cause Gillespie syndrome, (affected patients have ataxia and aniridia) and deletions in the gene cause a progressive adult onset form of ataxia known as SCA15. Spinocerebellar ataxia type 29 (SCA29; MIM #117360), also referred to as congenital non-progressive spinocerebellar ataxia, is a very rare disorder with less than 20 families reported to date. SCA29 is one of the few dominant Spinocerebellar ataxias that has very early onset, with some reports of patients showing symptoms at or shortly after

Drs Jillian Casey & Sally Ann Lynch together with neurologists, Dr Bryan Lynch, Temple Street Children’s Hospital & Dr Raymond Murphy, AMNCH Tallaght Hospital, investigated the genetic basis of a non progressive form of ataxia in a mother and her two children. The mother also had a corneal graft for keratoconus. Both of her affected children had pinpoint pupils.  MRI brain scans were normal with no evidence of cerebellar atrophy or other neuroimaging abnormalities, unlike other SCA29 cases.  Collaboration with a Japanese group led by Dr Mikoshiba from the RIKEN Brain Science Institute, Saitama, Japan, allowed functional studies to prove that the genetic variant found was pathogenic. The mutation was shown to cause a gain of function affect, likely due to calcium release. To date, ITPR1 mutation has been associated with a loss-of-function effect, likely due to reduced Calcium release. This is the first gain-of-function mechanism to be associated with ITPR1 related SCA29, providing novel insights into how enhanced Calcium release can also contribute to the pathogenesis of this neurological disorder.

The pathogenic gain of-function missense mutation was located within the suppressor region of ITPR1. This is the first report of a gain-of-function disease mutation in ITPR1 and contributes to our understanding of how variation in this gene can lead to neurological dysfunction.


A nove gain-of-function mutation in the ITPR1 suppressor domain causes spinocerebellar ataxia with altered Ca2+ signal patterns.

Jillian P Casey, Taisei Hirouchi, Chihiro Hisatsune, Bryan Lynch, Raymond Murphy, Aimee M Dunne, Akitoshi Miyamoto, Sean Ennis, Nick van der Spek, Bronagh O'Hici, Katsuhiko Mikoshiba and Sally Ann Lynch.

Original Article