期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 101, 期 3, 页码 441-450出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2017.07.015
关键词
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资金
- Center for Basic and Translational Research on Disorders of the Digestive System at The Rockefeller University through Leona M. and Harry B. Helmsley Charitable Trust
- Broad Institute [U54HG003067, UM1HG008900]
- Yale Center for Mendelian Disorders [U54HG006504]
- NIH from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program [P01HD070494, 1R01NS098004, R01NS048453, R01NS052455, UL1TR001866]
- Simons Foundation Autism Research Initiative [275275]
- Howard Hughes Medical Institute
- Qatar National Research Foundation NPRP [6-1463-3-351]
- NIH [K99NS089943]
- American Academy of Neurology Clinical Research Training Scholarship [2017-205]
- Joshua Deeth Foundation
- Wellcome Trust [097769/Z/11/Z]
- Wellcome Trust [097769/Z/11/Z] Funding Source: Wellcome Trust
Pontocerebellar hypoplasia (PCH) represents a group of recessive developmental disorders characterized by impaired growth of the pons and cerebellum, which frequently follows a degenerative course. Currently, there are 10 partially overlapping clinical subtypes and 13 genes known mutated in PCH. Here, we report biallelic TBC1D23 mutations in six individuals from four unrelated families manifesting a non-degenerative form of PCH. In addition to reduced volume of pons and cerebellum, affected individuals had microcephaly, psychomotor delay, and ataxia. In zebrafish, tbc1d23 morphants replicated the human phenotype showing hindbrain volume loss. TBC1D23 localized at the trans-Golgi and was regulated by the small GTPases Arl1 and Arl8, suggesting a role in trans-Golgi membrane trafficking. Altogether, this study provides a causative link between TBC1D23 mutations and PCH and suggests a less severe clinical course than other PCH subtypes.
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