TY - JOUR
T1 - Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia
AU - Marin-Valencia, Isaac
AU - Gerondopoulos, Andreas
AU - Zaki, Maha S.
AU - Ben-Omran, Tawfeg
AU - Almureikhi, Mariam
AU - Demir, Ercan
AU - Guemez-Gamboa, Alicia
AU - Gregor, Anne
AU - Issa, Mahmoud Y.
AU - Appelhof, Bart
AU - Roosing, Susanne
AU - Musaev, Damir
AU - Rosti, Basak
AU - Wirth, Sara
AU - Stanley, Valentina
AU - Baas, Frank
AU - Barr, Francis A.
AU - Gleeson, Joseph G.
N1 - Funding Information:
The authors thank all families for participation in this study. We thank Tessa van Dijk for coordinating data gathering from family 4572. Thanks to the Rockefeller and UCSD Microscopy Cores (P30 NS047101) for imaging support. I.M.-V. was sponsored by Pilot Grant awarded by the Center for Basic and Translational Research on Disorders of the Digestive System at The Rockefeller University through the generosity of the Leona M. and Harry B. Helmsley Charitable Trust. We thank the Broad Institute (U54HG003067 to E. Lander and UM1HG008900 to D. MacArthur) and the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton and M. Gunel). This work was supported by NIH grants P01HD070494, 1R01NS098004, R01NS048453, R01NS052455, and UL1TR001866 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program, the Simons Foundation Autism Research Initiative (275275), Howard Hughes Medical Institute (to J.G.G.), Qatar National Research Foundation NPRP 6-1463-3-351 (to T.B.-O. and J.G.G.), NIH grant K99NS089943 (to A.G.-G.), American Academy of Neurology Clinical Research Training Scholarship 2017-205 (to I.M.-V.), Joshua Deeth Foundation (to F.B.), and a Wellcome Trust Senior Investigator Award 097769/Z/11/Z (to F.A.B.).
Publisher Copyright:
© 2017 American Society of Human Genetics
PY - 2017/9/7
Y1 - 2017/9/7
N2 - 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.
AB - 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.
KW - TBC1D23
KW - ataxia
KW - intellectual disability
KW - microcephaly
KW - pontocerebellar hypoplasia
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U2 - 10.1016/j.ajhg.2017.07.015
DO - 10.1016/j.ajhg.2017.07.015
M3 - Article
C2 - 28823706
AN - SCOPUS:85027449509
SN - 0002-9297
VL - 101
SP - 441
EP - 450
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -