عنوان

Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.

Number

LA57n4q5z6

Title Proper

Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.

General Material Designation

[Article]

First Statement of Responsibility

Akizu, Naiara; Cantagrel, Vincent; Zaki, Maha S; Al-Gazali, Lihadh; Wang, Xin; Rosti, Rasim Ozgur; Dikoglu, Esra; Gelot, Antoinette Bernabe; Rosti, Basak; Vaux, Keith K; Scott, Eric M; Silhavy, Jennifer L; Schroth, Jana; Copeland, Brett; Schaffer, Ashleigh E; Gordts, Philip LSM; Esko, Jeffrey D; Buschman, Matthew D; et al.

Text of Note

Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain-containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.

Date of Publication

2015

Title

UC San Diego

Electronic name

[Article]

275578

a

Y