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1.
Am J Hum Genet. 2017 Sep 7;101(3):428-440. doi: 10.1016/j.ajhg.2017.07.010. Epub 2017 Aug 17.

Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development.

Author information

1
Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67400 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France; Université de Strasbourg, 67400 Illkirch, France.
2
Laboratoire de Diagnostic Génétique, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France; Centre National de la Recherche Scientifique, UMR7104, 67400 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France; Université de Strasbourg, 67400 Illkirch, France.
3
Department of Otorhinolaryngology-Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan.
4
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, 1985713834 Tehran, Iran.
5
Department of Pediatrics, Strasbourg University Hospital, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France.
6
Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
7
Department of Pediatrics, Strasbourg University Hospital, 67000 Strasbourg, France.
8
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Neurology, Oslo University Hospital, 0450 Oslo, Norway.
9
Laboratoire de Diagnostic Génétique, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France.
10
Centre National de Génotypage (CNG), 91000 Evry, France.
11
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
12
Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan.
13
Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad 44000, Pakistan; Allama Iqbal Medical College, University of Health Sciences, 54000 Lahore, Pakistan.
14
Institut Imagine, Bioinformatics Platform, Université Paris Descartes, 75015 Paris, France.
15
Max-Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
16
Laboratoire de Diagnostic Génétique, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400 Illkirch, France; Centre National de la Recherche Scientifique, UMR7104, 67400 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67400 Illkirch, France; Université de Strasbourg, 67400 Illkirch, France; Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, 67000 Strasbourg, France. Electronic address: chelly@igbmc.fr.

Abstract

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia.

KEYWORDS:

TBC1D23; microcephaly; pontocerebellar hypoplasia; small normally proportioned cerebellum

PMID:
28823707
PMCID:
PMC5590842
DOI:
10.1016/j.ajhg.2017.07.010
[Indexed for MEDLINE]
Free PMC Article
Icon for Elsevier Science Icon for PubMed Central
2.
Am J Hum Genet. 2017 Sep 7;101(3):441-450. doi: 10.1016/j.ajhg.2017.07.015. Epub 2017 Aug 17.

Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia.

Author information

1
Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
2
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
3
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, 12311 Cairo, Egypt.
4
Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, 3050 Doha, Qatar.
5
Gazi University, Department of Pediatric Neurology, 06500 Ankara, Turkey.
6
Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
7
Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA.
8
Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA; Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA.
9
Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA; Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, University of California, San Diego, San Diego, CA 92093, USA. Electronic address: jogleeson@ucsd.edu.

Abstract

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.

KEYWORDS:

TBC1D23; ataxia; intellectual disability; microcephaly; pontocerebellar hypoplasia

PMID:
28823706
PMCID:
PMC5590949
DOI:
10.1016/j.ajhg.2017.07.015
[Indexed for MEDLINE]
Free PMC Article
Icon for Elsevier Science Icon for PubMed Central

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