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A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course.

ABSTRACT: An intact and dynamic microtubule cytoskeleton is crucial for the development, differentiation, and maintenance of the mammalian cortex. Variants in a host of structural microtubulin-associated proteins have been identified to cause a wide spectrum of malformations of cortical development and alterations of microtubule dynamics have been recognized to cause or contribute to progressive neurodegenerative disorders. TBCD is one of the five tubulin-specific chaperones and is required for reversible assembly of the ?-/?-tubulin heterodimer. Recently, variants in TBCD, and one other tubulin-specific chaperone, TBCE, have been identified in patients with distinct progressive encephalopathy with a seemingly broad clinical spectrum. Here, we report the clinical, neuroradiological, and neuropathological features in eight patients originating from the Faroe Islands, who presented with an early onset, progressive encephalopathy with features of primary neurodegeneration, and a homogenous clinical course. These patients were homozygous for a TBCD missense variant c.[3099C>G]; p.(Asn1033Lys), which we show has a high carrier frequency in the Faroese population (2.6%). The patients had similar age of onset as the previously reported patients (n?=?24), but much shorter survival, which could be caused by either differences in supportive treatment, or alternatively, that shorter survival is intrinsic to the Faroese phenotype. We present a detailed description of the neuropathology and MR imaging characteristics of a subset of these patients, adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroese founder variant will allow targeted genetic diagnostics in patients of Faroese descent as well as improved genetic counseling and testing of at-risk couples.

SUBMITTER: Gronborg S

PROVIDER: S-EPMC6138752 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course.

Grønborg Sabine S Risom Lotte L Ek Jakob J Larsen Karen Bonde KB Scheie David D Petkov Yanko Y Larsen Vibeke André VA Dunø Morten M Joensen Fróði F Østergaard Elsebet E

European journal of human genetics : EJHG 20180619 10

An intact and dynamic microtubule cytoskeleton is crucial for the development, differentiation, and maintenance of the mammalian cortex. Variants in a host of structural microtubulin-associated proteins have been identified to cause a wide spectrum of malformations of cortical development and alterations of microtubule dynamics have been recognized to cause or contribute to progressive neurodegenerative disorders. TBCD is one of the five tubulin-specific chaperones and is required for reversible ...[more]

PMID: 29921875

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Project description:Microtubules are dynamic cytoskeletal elements coordinating and supporting a variety of neuronal processes, including cell division, migration, polarity, intracellular trafficking, and signal transduction. Mutations in genes encoding tubulins and microtubule-associated proteins are known to cause neurodevelopmental and neurodegenerative disorders. Growing evidence suggests that altered microtubule dynamics may also underlie or contribute to neurodevelopmental disorders and neurodegeneration. We report that biallelic mutations in TBCD, encoding one of the five co-chaperones required for assembly and disassembly of the αβ-tubulin heterodimer, the structural unit of microtubules, cause a disease with neurodevelopmental and neurodegenerative features characterized by early-onset cortical atrophy, secondary hypomyelination, microcephaly, thin corpus callosum, developmental delay, intellectual disability, seizures, optic atrophy, and spastic quadriplegia. Molecular dynamics simulations predicted long-range and/or local structural perturbations associated with the disease-causing mutations. Biochemical analyses documented variably reduced levels of TBCD, indicating relative instability of mutant proteins, and defective β-tubulin binding in a subset of the tested mutants. Reduced or defective TBCD function resulted in decreased soluble α/β-tubulin levels and accelerated microtubule polymerization in fibroblasts from affected subjects, demonstrating an overall shift toward a more rapidly growing and stable microtubule population. These cells displayed an aberrant mitotic spindle with disorganized, tangle-shaped microtubules and reduced aster formation, which however did not alter appreciably the rate of cell proliferation. Our findings establish that defective TBCD function underlies a recognizable encephalopathy and drives accelerated microtubule polymerization and enhanced microtubule stability, underscoring an additional cause of altered microtubule dynamics with impact on neuronal function and survival in the developing brain.

Dataset Information

A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course.

Publications

A Faroese founder variant in TBCD causes early onset, progressive encephalopathy with a homogenous clinical course.

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