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

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.

Citation

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 Napolitano, Ghada M Abdel-Salam, R Koksal Ozgul, Mahmut Samil Sagıroglu, 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. Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction. Nature genetics. 2015 May;47(5):528-34

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PMID: 25848753

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