Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction
Date
2015Author
Schaffer, Ashleigh E.
Schroth, Jana
Copeland, Brett
Gordts, Philip L. S. M.
Esko, Jeffrey D.
Buschman, Matthew D.
Field, Seth J.
Napolitano, Gennaro
Abdel-Salam, Ghada M.
ÖZGÜL, RIZA KÖKSAL
Sagiroglu, Mahmut Samil
Azam, Matloob
Ismail, Samira
Aglan, Mona
Selim, Laila
Mahmoud, Iman G.
Abdel-Hadi, Sawsan
El Badawy, Amera
Sadek, Abdelrahim A.
Mojahedi, Faezeh
Masri, Amira
Bastaki, Laila
Temtamy, Samia
Mueller, Ulrich
Desguerre, Isabelle
Casanova, Jean-Laurent
DURSUN, ALİ
Gunel, Murat
Gabriel, Stacey B.
de Lonlay, Pascale
Gleeson, Joseph G.
Kayserili, Hulya
Rosti, Rasim Ozgur
Akizu, Naiara
Cantagrel, Vincent
Zaki, Maha S.
Al-Gazali, Lihadh
Wang, Xin
Dikoglu, Esra
Gelot, Antoinette Bernabe
Rosti, Basak
Vaux, Keith K.
Scott, Eric M.
Silhavy, Jennifer L.
Metadata
Show full item recordAbstract
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.
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