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

Naiara Akizu, Vincent Cantagrel, Maha S. Zaki, Lihadh Al-Gazali, Xin Wang, Rasim Ozgur Rosti, Esra Dikoglu, Antoinette Bernabe Gelot, Basak Rosti, Keith K. Vaux, Eric M. Scott, Jennifer L. Silhavy, Jana Schroth, Brett Copeland, Ashleigh E. Schaffer, Philip L.S.M. Gordts, Jeffrey D. Esko, Matthew D. Buschman, Seth J. Field, Gennaro NapolitanoGhada M. Abdel-Salam, R. Koksal Ozgul, Mahmut Samil Saglroglu, Matloob Azam, Samira Ismail, Mona Aglan, Laila Selim, Iman G. Mahmoud, Sawsan Abdel-Hadi, Amera El Badawy, Abdelrahim A. Sadek, Faezeh Mojahedi, Hulya Kayserili, Amira Masri, Laila Bastaki, Samia Temtamy, Ulrich Müller, Isabelle Desguerre, Jean Laurent Casanova, Ali Dursun, Murat Gunel, Stacey B. Gabriel, Pascale De Lonlay, Joseph G. Gleeson

Research output: Contribution to journalArticlepeer-review

92 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)528-534
Number of pages7
JournalNature Genetics
Issue number5
Publication statusPublished - May 30 2015

ASJC Scopus subject areas

  • Genetics


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