MAP4-dependent regulation of microtubule formation affects centrosome, cilia, and golgi architecture as a central mechanism in growth regulation

Zahnleiter D, Hauer N, Keßler K, Uebe S, Sugano Y, Neuhauss SCF, Gießl A, Ekici AB, Blessing H, Sticht H, Dörr HG, Reis A, Thiel C (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Human Mutation Wiley-Blackwell

Book Volume: 36

Pages Range: 87-97

Journal Issue: 1

DOI: 10.1002/humu.22711

Abstract

Numerous genes are involved in human growth regulation. Recently, autosomal-recessive inherited variants in centrosomal proteins have been identified in Seckel syndrome, primary microcephaly, or microcephalic osteodysplastic primary dwarfism. Common hallmarks of these syndromic forms are severe short stature and microcephaly. In a consanguineous family with two affected children with severe growth retardation and normocephaly, we used homozygosity mapping and next-generation sequencing to identify a homozygous MAP4 variant. MAP4 is a major protein for microtubule assembly during mitosis. High-expression levels in the somite boundaries of zebrafish suggested a role in growth and body segment patterning. The identified variant affects binding sites of kinases necessary for dynamic instability of microtubule formation. We found centrosome amplifications in mitotic fibroblast cells in vivo and in vitro. These numeric centrosomal aberrations were also present during interphase resulting in aberrant ciliogenesis. Furthermore, affected cells showed a dysfunction of the microtubule-dependent assembly of the Golgi apparatus, indicated by a significant lack of compactness of Golgi membranes. These observations demonstrated that MAP4 mutations contribute to the clinical spectrum of centrosomal defects and confirmed the complex role of a centrosomal protein in centrosomal, ciliary, and Golgi regulation associated with severe short stature.

Authors with CRIS profile

Diana Zahnleiter Lehrstuhl für Humangenetik Nadine Hauer Lehrstuhl für Humangenetik Kristin Keßler Lehrstuhl für Humangenetik Steffen Uebe Institute of Human Genetics Andreas Gießl Lehrstuhl für Tierphysiologie Arif Bülent Ekici Institute of Human Genetics Heinrich Sticht Professur für Bioinformatik Helmuth-Günther Dörr Professur für Kinderheilkunde mit dem Schwerpunkt Kinder-Endokrinologie und Diabetologie (Stiftungsprofessur) André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Christian Thiel Medizinische Fakultät

Involved external institutions

University of Zurich / Universität Zürich (UZH) CH Switzerland (CH)

How to cite

APA:

Zahnleiter, D., Hauer, N., Keßler, K., Uebe, S., Sugano, Y., Neuhauss, S.C.F.,... Thiel, C. (2015). MAP4-dependent regulation of microtubule formation affects centrosome, cilia, and golgi architecture as a central mechanism in growth regulation. Human Mutation, 36(1), 87-97. https://dx.doi.org/10.1002/humu.22711

MLA:

Zahnleiter, Diana, et al. "MAP4-dependent regulation of microtubule formation affects centrosome, cilia, and golgi architecture as a central mechanism in growth regulation." Human Mutation 36.1 (2015): 87-97.

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