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

Serdal Güngör ,Yavuz Oktay,Burcu Ekinci,Ezgi Karaca,Bilge Özgör,Andreas Roos,Daniel G Macarthur,Isabelle Vernos,Rita Horvath,Denisa Hathazi,Mahmut Aslan,Ana Töpf,Steven S Laurie ,Sergi Beltrán ,Nora Szabó ,Hanns Lochmüller ,Uluç Yış ,B Sunitha ,Ahmet Yaramış ,Álvaro Aranguren‐Ibáñez ,İpek Polat Kalafatcilar ,Ece Sönmezler ,Evrim Yılmaz ,Semra Hız

doi:10.1016/j.isci.2020.101948

Abstract

SummaryMicrotubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-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 γ-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 γ-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 γ-tubulin complex to the development of the central nervous system in humans.

Highlights

Microtubules (MTs) are dynamic, cytoskeletal polymers crucial for cortical development and neuronal migration
We studied the localization of several components of the g-TuRC complex in control and TUBGCP2 mutated human fibroblasts, as well as the levels of the TUBGCP2 protein along the cell cycle, and performed proteomics and structural modeling studies to explore the functional effect of the mutant TUBGCP2 protein in neurodegeneration
Patients and family members were recruited at the Department of Paediatric Neurology, Malatya (Turkey) after informed consent

Summary

Introduction

Microtubules (MTs) are dynamic, cytoskeletal polymers crucial for cortical development and neuronal migration. Mutations in several genes encoding alpha-tubulin (TUBA1A), beta-tubulin (TUBB2A, TUBB2B, TUBB3, TUBB4A, TUBB), and gamma-tubulin (g-tubulin) (TUBG1) isoforms have been associated with a wide range of brain malformations including lissencephaly, polymicrogyria, microlissencephaly, and simplified gyration (Romaniello et al, 2018). Mutations in different tubulin genes cause various phenotypes (Table 1). Alpha-tubulin and g-tubulin gene mutations predominantly result in lissencephaly spectrum diseases (Romaniello et al, 2018). Beta-tubulin gene mutations may show normal cortical pattern; TUBB4A is predominantly associated with hypomyelination and cerebellar and brainstem atrophy (Blumkin et al, 2014). TUBB2B and TUBB3 mutations seem to be more related to polymicroglial patterns. And ocular malformations are commonly seen in beta-tubulin (TUBB) defects (Francis and Belvindrah, 2018; Romaniello et al, 2018)

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