PUBLICATION

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

Authors
Akizu, N., Cantagrel, V., Zaki, M.S., Al-Gazali, L., Wang, X., Rosti, R.O., Dikoglu, E., Gelot, A.B., Rosti, B., Vaux, K.K., Scott, E.M., Silhavy, J.L., Schroth, J., Copeland, B., Schaffer, A.E., Gordts, P.L., Esko, J.D., Buschman, M.D., Field, S.J., Napolitano, G., Abdel-Salam, G.M., Ozgul, R.K., Sagıroglu, M.S., Azam, M., Ismail, S., Aglan, M., Selim, L., Mahmoud, I.G., Abdel-Hadi, S., Badawy, A.E., Sadek, A.A., Mojahedi, F., Kayserili, H., Masri, A., Bastaki, L., Temtamy, S., Müller, U., Desguerre, I., Casanova, J.L., Dursun, A., Gunel, M., Gabriel, S.B., de Lonlay, P., Gleeson, J.G.
ID
ZDB-PUB-150408-10
Date
2015
Source
Nature Genetics   47(5): 528-34 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Animals
  • Atrophy/genetics
  • Autophagy
  • Cerebellar Diseases/genetics*
  • Cerebellum/pathology*
  • Child, Preschool
  • Female
  • Gene Frequency
  • Humans
  • Infant
  • Lod Score
  • Lysosomal Storage Diseases/genetics
  • Lysosomes/metabolism*
  • Male
  • Mutation
  • Phagosomes/metabolism*
  • Sorting Nexins/genetics*
  • Spinocerebellar Ataxias/genetics*
  • Syndrome
  • Zebrafish
PubMed
25848753 Full text @ Nat. Genet.
Abstract
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping