TY - JOUR
T1 - Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction
AU - Akizu, Naiara
AU - Cantagrel, Vincent
AU - Zaki, Maha S.
AU - Al-Gazali, Lihadh
AU - Wang, Xin
AU - Rosti, Rasim Ozgur
AU - Dikoglu, Esra
AU - Gelot, Antoinette Bernabe
AU - Rosti, Basak
AU - Vaux, Keith K.
AU - Scott, Eric M.
AU - Silhavy, Jennifer L.
AU - Schroth, Jana
AU - Copeland, Brett
AU - Schaffer, Ashleigh E.
AU - Gordts, Philip L.S.M.
AU - Esko, Jeffrey D.
AU - Buschman, Matthew D.
AU - Field, Seth J.
AU - Napolitano, Gennaro
AU - Abdel-Salam, Ghada M.
AU - Ozgul, R. Koksal
AU - Saglroglu, Mahmut Samil
AU - Azam, Matloob
AU - Ismail, Samira
AU - Aglan, Mona
AU - Selim, Laila
AU - Mahmoud, Iman G.
AU - Abdel-Hadi, Sawsan
AU - Badawy, Amera El
AU - Sadek, Abdelrahim A.
AU - Mojahedi, Faezeh
AU - Kayserili, Hulya
AU - Masri, Amira
AU - Bastaki, Laila
AU - Temtamy, Samia
AU - Müller, Ulrich
AU - Desguerre, Isabelle
AU - Casanova, Jean Laurent
AU - Dursun, Ali
AU - Gunel, Murat
AU - Gabriel, Stacey B.
AU - De Lonlay, Pascale
AU - Gleeson, Joseph G.
N1 - Funding Information:
We thank Y. Itan and B. Boisson for sequencing, T. Meerloo and A. Schmitt for electron microscopy support, the Sanford Burnham Institute for iPSC reprogramming, and A.M. Cuervo and M. Farquhar for comments and suggestions. Analysis was performed by the University of California San Diego Glycotechnology Core and the University of California San Diego Microscopy Imaging Core. This work was supported by US National Institutes of Health grants P01HD070494 and R01NS048453 and the Howard Hughes Medical Institute (to J.G.G.), US National Institutes of Health grant K99NS089859-01 (to N.A.), Broad Institute grant U54HG003067, Yale Center for Mendelian Disorders grant U54HG006504 (to M.G.), INSERM, Paris Descartes University, the St. Giles Foundation, and the Candidoser Association and Howard Hughes Medical Institute (to J.-L.C.), the Scientific and Technology Research Council of Turkey (grant TÜBİTAK-SBAG, 111S217, grant TÜBİTAK-BİLGEM-UEKAE, K030-T439) and the Turkey Republic Ministry of Development (grant TRMOD, 108S420) (to A.D.).
Publisher Copyright:
© 2015 Nature America, Inc.
PY - 2015/5/30
Y1 - 2015/5/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84929134737&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84929134737&partnerID=8YFLogxK
U2 - 10.1038/ng.3256
DO - 10.1038/ng.3256
M3 - Article
C2 - 25848753
AN - SCOPUS:84929134737
SN - 1061-4036
VL - 47
SP - 528
EP - 534
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -