Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders

Mitani, Tadahiro; Punetha, Jaya; Akalın, İbrahim; Pehlivan, Davut; Dawidziuk, Mateusz; Akdemir, Zeynep Coban; Yılmaz, Sarenur; Aslan, Ezgi; Hunter, Jill V.; Hijazi, Hadia; Grochowski, Christopher M.; Jhangiani, Shalini N.; Karaca, Ender; Fatih, Jawid M.; Iwanowski, Piotr; Gambin, Tomasz; Własienko, Paweł; Goszczańska-Ciuchta, Alicja; Bekiesińska‐Figatowska, Monika; Hosseini, Masoumeh; Arzhangi, Sanaz; Najmabadi, Hossein; Rosenfeld, Jill A.; Du, Haowei; Marafi, Dana; Blasér, Susan; Teitelbaum, Ronni; Silver, Rachel; Posey, Jennifer E.; Ropers, Hans‐Hilger; Gibbs, Richard A.; Wiszniewski, Wojciech; Lupski, James R.; Chitayat, David; Kahrizi, Kimia; Gawliński, Paweł

doi:10.1016/j.ajhg.2019.09.017

Cited by 26 publications

(26 citation statements)

References 36 publications

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“…Within cells de novo assembly of new microtubules, that is microtubule nucleation, is kinetically unfavourable and is templated and catalysed by multi-protein γ-tubulin ring complexes (γ-TuRCs) ( Tovey and Conduit, 2018 ). Knockdown of γ-TuRCs within model systems affects dynamic microtubules in all neuronal compartments ( Nguyen et al, 2014 ; Ori-McKenney et al, 2012 ; Sánchez-Huertas et al, 2016 ; Yamada and Hayashi, 2019 ; Yau et al, 2014 ) and mutations in γ-TuRC genes have been linked to human neurodevelopmental disorders ( Bahi-Buisson et al, 2014 ; Mitani et al, 2019 ; Poirier et al, 2013 ). γ-TuRCs are typically inactive until they are recruited to specific sites within cells, such as microtubule organising centres (MTOCs), the cytosol around mitotic chromatin, or the sides of pre-existing microtubules via binding to Augmin/HAUS complexes ( Farache et al, 2018 ; Lin et al, 2015 ; Meunier and Vernos, 2016 ; Sanchez and Feldman, 2017 ; Teixido-Travesa et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Microtubules originate asymmetrically at the somatic golgi and are guided via Kinesin2 to maintain polarity within neurons

Mukherjee

Brooks

Bernard

et al. 2020

eLife

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Neurons contain polarised microtubule arrays essential for neuronal function. How microtubule nucleation and polarity are regulated within neurons remains unclear. We show that γ-tubulin localises asymmetrically to the somatic Golgi within Drosophila neurons. Microtubules originate from the Golgi with an initial growth preference towards the axon. Their growing plus ends also turn towards and into the axon, adding to the plus-end-out microtubule pool. Any plus ends that reach a dendrite, however, do not readily enter, maintaining minus-end-out polarity. Both turning towards the axon and exclusion from dendrites depend on Kinesin-2, a plus-end-associated motor that guides growing plus ends along adjacent microtubules. We propose that Kinesin-2 engages with a polarised microtubule network within the soma to guide growing microtubules towards the axon; while at dendrite entry sites engagement with microtubules of opposite polarity generates a backward stalling force that prevents entry into dendrites and thus maintains minus-end-out polarity within proximal dendrites.

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Section: Introductionmentioning

confidence: 99%

Microtubules originate asymmetrically at the somatic golgi and are guided via Kinesin2 to maintain polarity within neurons

Mukherjee

Brooks

Bernard

et al. 2020

eLife

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“…Cognitive impairment is more severe in PLK4 and TUBGCP6 described patients than in other MCPH syndromes, such as TUBGCP5 and KIF-11, where the neurological phenotype is overall milder and less severe cortical involvement is displayed [12, 13]. On the other hand, TUBGCP2 is another recently described entity, where abnormalities in cortical development seem to be consistent [14].…”

Section: Discussion/conclusionmentioning

confidence: 99%

Primary Dwarfism, Microcephaly, and Chorioretinopathy due to a PLK4 Mutation in Two Siblings

et al. 2020

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Introduction: Primary autosomal recessive microcephalies (MCPHs) are characterized by primary dwarfism with MCPH and may present delayed psychomotor development and visual impairment. Biallelic loss of function variants in the PLK4 gene, which encodes the polo-like kinase 4 protein involved in centriole biogenesis, has been recently identified in several patients with MCPH and various ethnic backgrounds. Case Presentation: Here, we describe 2 siblings of different sex from Equatorial Guinea harboring a homozygous frameshift mutation in PLK4 (c.1299_1303del, p.Phe433Leufs*6). A Seckel syndrome spectrum phenotype was present in both siblings, with short stature, severe MCPH, reduced brain volume, and distinctive facial features. They also presented severe intellectual disability, lissencephaly/pachygyria, subependymal heterotopia, and ophthalmological impairment. One of them suffered from deafness, and scoliosis was observed in the other. Discussion/Conclusion: Biallelic variants in PLK4 lead to a syndrome where severe short stature, MCPH, and cognitive impairment are constant features. However, ocular, skeletal, and other neurological manifestations can vary upon the same genetic basis.

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“…Mutations in several components of the g-tubulin complex including TUBGCP4, TUBGCP5, and TUBGCP6 have been previously reported in human neurodevelopmental diseases often associated with microcephaly (Maver et al, 2019;Mitani et al, 2019;Scheidecker et al, 2015) (Da Palma et al, 2020;Hull et al, 2019;Maver et al, 2019;Mitani et al, 2019). Most of these mutations led to a loss of function and reduced levels of several GCP proteins (Table 1).…”

Section: Introductionmentioning

confidence: 94%

Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease

et al. 2021

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Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (g-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in TUBGCP2 encoding the g-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of g-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the g-tubulin complex to the development of the central nervous system in humans.

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Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders

Cited by 26 publications

References 36 publications

Microtubules originate asymmetrically at the somatic golgi and are guided via Kinesin2 to maintain polarity within neurons

Microtubules originate asymmetrically at the somatic golgi and are guided via Kinesin2 to maintain polarity within neurons

Primary Dwarfism, Microcephaly, and Chorioretinopathy due to a PLK4 Mutation in Two Siblings

Autosomal recessive variants in TUBGCP2 alter the γ-tubulin ring complex leading to neurodevelopmental disease

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