MAP4 defect underlines centrosomal organization as a central mechanism in growth regulation. C. T. Thiel1, D. Zahnleiter1, N. Hauer1, K. Kessler1, Y. Sugano2, S. Neuhaus2, A. B. Ekici1, H. Blessing3, H. Sticht4, H.-G. Doerr3, A. Reis1 1) Institute of Human Genetics, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany; 2) Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland; 3) Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany; 4) Institute of Biochemistry, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.

   Shortness of stature is a common medical concern in childhood, since 3 % of the general population present with a body height below -2 SD scores (SDS). After excluding already known defects the underlying cause remains unknown in approximately 80 % of patients. Recently, mutations in centrosomal proteins have been associated with severe syndromal forms of short stature with microcephaly. In a consanguineous family with two affected children with severe growth retardation of -7 SDS and relative macrocephaly (-2 SDS) we used genome wide homozygosity mapping and whole exome sequencing to identify a homozygous missense mutation in the coding region of the MAP4 gene. This mutation was excluded in 372 control individuals, the 1000genomes project or ESP5400, and segregated in the family. We performed a quantitative real-time RT-PCR and detected a 70 % reduced MAP4 expression level in the patient compared to healthy controls indicating a reduced stability of the mutant transcript. MAP4 is a major protein for microtubuli assembly during mitosis and ubiquitously expressed. The identified mutation in our patients led to a new phosphorylation site which is most likely phosphorylated by kinases in cell cycle regulation like cdk1 and predicted to alter microtubuli organization. Defects in the cell cycle were confirmed in the patient fibroblast cell line by detecting centrosome amplifications in 40 % of the mitotic cells. These numeric centrosomal aberrations were also present during interphase where centrosomes form the basal body initiating ciliogenesis. The identification of cilia duplications and disturbed cilia associated pathways in the patient cells confirmed a combined effect on mitosis and ciliogenesis. High expression levels in the somite boundaries of the zebrafish proposed a role in growth and body segment patterning by MAP4. We noted significant overlap of the patients phenotype with Seckel syndrome and Microcephalic Osteodysplastic Dwarfism type Majewski also caused by defects in centrosomal proteins. Surprisingly, our patients did present with relative macrocephaly. This observation is explained by the only brain expressed MAP2 gene, likely to compensate the MAP4 defect in our patients. Therefore, our results confirmed dysregulation of centrosomal proteins to be associated with severe short stature, whereas disturbed neuron development, leading to microcephaly, underlies complex regulation mechanisms.

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