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Hum Mol Genet. 2019 Jul 31. pii: ddz186. doi: 10.1093/hmg/ddz186. [Epub ahead of print]

Defective tubulin detyrosination causes structural brain abnormalities with cognitive deficiency in humans and mice.

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NIHR Oxford BRC, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Univ. Grenoble Alpes, Inserm, U1216, CEA, CNRS, Grenoble Institut Neurosciences, 38000 Grenoble, France.
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
MMDN, Univ. Montpellier, INSERM, EPHE, UMR_S1198, Montpellier, France.
South East Thames Regional Genetics Unit, Guys and St Thomas NHS Trust, London, UK.
Department of Neuroradiology, Kings College Hospital, Denmark Hill, London SE5 9RS, UK.
Ministry of Health, Kuwait Medical Genetics Center, Sulaibikhat 80901, Kuwait.
Department of Paediatric Neurology, John Radcliffe Hospital, Oxford, UK.
Community Paediatrics, Upton Hospital, Slough, UK.
Clinical Biochemistry, Wexham Park Hospital, Slough, UK.
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Centogene AG, 18055 Rostock, Germany.


Reversible detyrosination of tubulin, the building block of microtubules, is crucial for neuronal physiology. Enzymes responsible for detyrosination were recently identified as complexes of vasohibins 1 or 2 with small vasohibin-binding protein (SVBP). Here we report three consanguineous families, each containing multiple individuals with biallelic inactivation of SVBP caused by truncating variants (p.Q28* and p.K13Nfs*18). Affected individuals show brain abnormalities with microcephaly, intellectual disability and delayed gross motor and speech development. Immunoblot testing in cells with pathogenic SVBP variants demonstrated that the encoded proteins were unstable and non-functional, resulting in a complete loss of vasohibin detyrosination activity. Svbp knockout mice exhibit drastic accumulation of tyrosinated tubulin and a reduction of detyrosinated tubulin in brain tissue. Similar alterations in tubulin tyrosination levels were observed in cultured neurons and associated with defects in axonal differentiation and architecture. Morphological analysis of the Svbp knockout mouse brains by anatomical MRI showed a broad impact of SVBP loss, with a 7% brain volume decrease, numerous structural defects and a 30% reduction of some white matter tracts. Svbp knockout mice display behavioral defects, including mild hyperactivity, lower anxiety and impaired social behavior. They do not, however, show prominent memory defects. Thus, SVBP deficient mice recapitulate several features observed in human patients. Altogether, our data demonstrate that deleterious variants in SVBP cause this neurodevelopmental pathology, by leading to a major change in brain tubulin tyrosination and alteration of microtubule dynamics and neuron physiology.


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