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

被引：97

作者：

Akizu, Naiara ^{[1
,2
,3
]}

Cantagrel, Vincent ^{[4
]}

Zaki, Maha S. ^{[5
]}

Al-Gazali, Lihadh ^{[6
]}

Wang, Xin ^{[1
,2
]}

Rosti, Rasim Ozgur ^{[1
,2
]}

Dikoglu, Esra ^{[1
,2
]}

Gelot, Antoinette Bernabe ^{[7
,8
]}

Rosti, Basak ^{[1
,2
]}

Vaux, Keith K. ^{[1
,2
]}

Scott, Eric M. ^{[1
,2
]}

Silhavy, Jennifer L. ^{[1
,2
]}

Schroth, Jana ^{[1
,2
]}

Copeland, Brett ^{[1
,2
]}

Schaffer, Ashleigh E. ^{[1
,2
]}

Gordts, Philip L. S. M. ^{[9
]}

Esko, Jeffrey D. ^{[9
]}

Buschman, Matthew D. ^{[10
]}

Field, Seth J. ^{[10
]}

Napolitano, Gennaro ^{[11
]}

Abdel-Salam, Ghada M. ^{[5
]}

Ozgul, R. Koksal ^{[12
]}

Sagiroglu, Mahmut Samil ^{[13
]}

Azam, Matloob ^{[14
]}

Ismail, Samira ^{[5
]}

Aglan, Mona ^{[5
]}

Selim, Laila ^{[15
]}

Mahmoud, Iman G. ^{[15
]}

Abdel-Hadi, Sawsan ^{[15
]}

El Badawy, Amera ^{[15
]}

Sadek, Abdelrahim A. ^{[16
]}

Mojahedi, Faezeh ^{[17
]}

Kayserili, Hulya ^{[18
]}

Masri, Amira ^{[19
]}

Bastaki, Laila ^{[20
]}

Temtamy, Samia ^{[5
]}

Mueller, Ulrich ^{[3
]}

Desguerre, Isabelle ^{[21
]}

Casanova, Jean-Laurent ^{[2
,22
,23
]}

Dursun, Ali ^{[24
]}

Gunel, Murat ^{[25
,26
,27
]}

Gabriel, Stacey B. ^{[28
]}

de Lonlay, Pascale ^{[29
]}

Gleeson, Joseph G. ^{[1
,2
,30
]}

机构：

[1] Rockefeller Univ, Lab Pediat Brain Dis, New York, NY 10021 USA

[2] Howard Hughes Med Inst, Chevy Chase, MD USA

[3] Scripps Res Inst, Dorris Neurosci Ctr, La Jolla, CA 92037 USA

[4] Hop Necker Enfants Malad, INSERM, Inst Imagine, U1163, Paris, France

[5] Natl Res Ctr, Dept Clin Genet, Human Genet & Genome Res Div, Cairo, Egypt

[6] United Arab Emirates Univ, Dept Pediat, Coll Med & Hlth Sci, Abu Dhabi, U Arab Emirates

[7] Hop Armand Trousseau, Assistance Publ Hop Paris, UF Genet Dev, Dept Genet,Neuropathol, Paris, France

[8] INSERM, Inst Neurobiol Mediterranee INMED, U901, F-13258 Marseille, France

[9] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[10] Univ Calif San Diego, Dept Med, Div Endocrinol & Metab, La Jolla, CA 92093 USA

[11] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA

[12] Hacettepe Univ, Inst Child Hlth, Pediat Metab, Ankara, Turkey

[13] Tubitak Bilgem Uekae, Gebze, Turkey

[14] Wah Med Coll, Wah, Pakistan

[15] Cairo Univ, Childrens Hosp, Dept Pediat Neurol, Cairo, Egypt

[16] Sohag Univ, Fac Med, Pediat Neurol Dept, Sohag, Egypt

[17] Mashhad Med Genet Counseling Ctr, Mashhad, Iran

[18] Istanbul Univ, Istanbul Fac Med, Med Genet Dept, Istanbul, Turkey

[19] Univ Jordan, Dept Pediat, Div Child Neurol, Amman, Jordan

[20] Matern Hosp, Kuwait Med Genet Ctr, Safat, Kuwait

[21] Paris Descartes Univ, Necker Enfants Malad Hosp, Dept Pediat Neurol, Paris, France

[22] Univ Paris 05, Inst Imagine, Genet Humaine Malad Infect, INSERM,U1163, Paris, France

[23] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, New York, NY 10021 USA

[24] Hacettepe Univ, Fac Med, Pediat Metab, TR-06100 Ankara, Turkey

[25] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT USA

[26] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA

[27] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA

[28] Broad Inst MIT & Harvard, Cambridge, MA USA

[29] Paris Descartes Univ, Necker Enfants Malades Hosp, Assistance Publ Hop Paris, Reference Ctr Inherited Metab Dis, Paris, France

[30] New York Genome Ctr, New York, NY USA

来源：

NATURE GENETICS | 2015年 / 47卷 / 05期

基金：

美国国家卫生研究院;

关键词：

NEURODEGENERATIVE DISEASE; INTELLECTUAL DISABILITY; ATAXIA; SUPPRESSION; DISCOVERY; DEATH; MODEL;

D O I：

10.1038/ng.3256

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：528 / U137

页数：9

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