PUBLICATION

MAP4 Dependent Regulation of Microtubule Formation Affects Centrosome, Cilia and Golgi Architecture as A Central Mechanism in Growth Regulation

Authors
Zahnleiter, D., Hauer, N.N., Kessler, K., Uebe, S., Sugano, Y., Neuhauss, S.C., Giessl, A., Ekici, A.B., Blessing, H., Sticht, H., Dörr, H.G., Reis, A., Thiel, C.T.
ID
ZDB-PUB-141018-3
Date
2015
Source
Human Mutation   36(1): 87-97 (Journal)
Registered Authors
Neuhauss, Stephan, Sugano, Yuya
Keywords
MAP4, Microcephaly, Seckel syndrome, centrosomal amplification, centrosome, growth deficit, short stature
MeSH Terms
  • Animals
  • Binding Sites
  • Cells, Cultured
  • Centrosome/metabolism*
  • Cilia/metabolism*
  • Golgi Apparatus/metabolism*
  • Growth Disorders/genetics*
  • Homozygote
  • Humans
  • Microtubule-Associated Proteins/chemistry
  • Microtubule-Associated Proteins/genetics*
  • Microtubule-Associated Proteins/metabolism*
  • Microtubules/metabolism
  • Mutation, Missense
  • Republic of North Macedonia
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed
25323976 Full text @ Hum. Mutat.
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. This article is protected by copyright. All rights reserved.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping