Novel Mutations in the Asparagine Synthetase Gene (ASNS) Associated With Microcephaly

Frontiers in Genetics

Johannes Hirrlinger¹  Ulrike Winkler²  Susanne Köhler²  Knut Krohn³  Ria Schönauer⁴  Anna Seidel⁴  Ruth Stassart⁵  Jürgen Klammt⁶  Dorit Schleinitz⁷  Peter Kovacs⁷  John T. Heiker⁸  Joanna Bialek⁹  Katrin Hoffmann⁹  Petra G. Hirrlinger^1,10 

[1]0Department of Neurogenetics, Max-Planck-Institute for Experimental Medicine, Göttingen, Germany

[2]Carl-Ludwig-Institute for Physiology, Faculty of Medicine, University of Leipzig, Leipzig, Germany

[3]Core Unit DNA Technologien, Faculty of Medicine, University of Leipzig, Leipzig, Germany

[4]Division of Nephrology, Department of Internal Medicine, Leipzig University Medical Center, University of Leipzig, Leipzig, Germany

[5]Division of Neuropathology, Department of Diagnostic, Leipzig University Medical Center, University of Leipzig, Leipzig, Germany

[6]Hospital for Children and Adolescents, Faculty of Medicine, University of Leipzig, Leipzig, Germany

[7]IFB AdiposityDiseases, Leipzig University Medical Center, University of Leipzig, Leipzig, Germany

[8]Institute of Biochemistry, Faculty of Life Sciences, University of Leipzig, Leipzig, Germany

[9]Institute of Human Genetics, Martin Luther University Halle-Wittenberg, Halle, Germany

[10]Medizinisch-Experimentelles Zentrum, Faculty of Medicine, University of Leipzig, Leipzig, Germany

关键词: microcephaly;    asparagine synthetase;    mutation;    compound heterozygous;    exome sequencing;    genetic variants;   

DOI  :  10.3389/fgene.2018.00245

来源: DOAJ

【 摘 要 】

Microcephaly is a devastating condition defined by a small head and small brain compared to the age- and sex-matched population. Mutations in a number of different genes causative for microcephaly have been identified, e.g., MCPH1, WDR62, and ASPM. Recently, mutations in the gene encoding the enzyme asparagine synthetase (ASNS) were associated to microcephaly and so far 24 different mutations in ASNS causing microcephaly have been described. In a family with two affected girls, we identified novel compound heterozygous variants in ASNS (c.1165G > C, p.E389Q and c.601delA, p.M201Wfs∗28). The first mutation (E389Q) is a missense mutation resulting in the replacement of a glutamate residue evolutionary conserved from Escherichia coli to Homo sapiens by glutamine. Protein modeling based on the known crystal structure of ASNS of E. coli predicted a destabilization of the protein by E389Q. The second mutation (p.M201Wfs∗28) results in a premature stop codon after amino acid 227, thereby truncating more than half of the protein. The novel variants expand the growing list of microcephaly causing mutations in ASNS.

【 授权许可】

Unknown