Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Schleinitz D

PROVIDER: S-EPMC6053511 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Schleinitz Dorit D Seidel Anna A Stassart Ruth R Klammt Jürgen J Hirrlinger Petra G PG Winkler Ulrike U Köhler Susanne S Heiker John T JT Schönauer Ria R Bialek Joanna J Krohn Knut K Hoffmann Katrin K Kovacs Peter P Hirrlinger Johannes J

Frontiers in genetics 20180713

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 affec ...[more]

PMID: 30057589

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Project description:BackgroundAsparagine synthetase deficiency (ASNSD) is a rare pediatric congenital disorder that clinically manifests into severe progressive microcephaly, global developmental delay, spastic quadriplegia, and refractory seizures. ASNSD is caused by inheritable autosomal recessive mutations in the asparagine synthetase (ASNS) gene.MethodsWe performed whole-exome sequencing using the patient's peripheral blood, and newly discovered mutations were subsequently verified in the patient's parents via Sanger sequencing. Software-based bioinformatics analyses (protein sequence conservation analysis, prediction of protein phosphorylation sites, protein structure modeling, and protein stability prediction) were performed to investigate and deduce their downstream effects.ResultsIn this article, we summarized all the previously reported cases of ASNSD and that of a Chinese girl who was clinically diagnosed with ASNSD, which was later confirmed via genetic testing. Whole-exome sequencing revealed two compound heterozygous missense mutations within the ASNS (c.368T > C, p.F123S and c.1649G > A, p.R550H). The origin of the two mutations was also verified in the patient's parents via Sanger sequencing. The mutation c.368T > C (p.F123S) was discovered and confirmed to be novel and previously unreported. Using software-based bioinformatics analyses, we deduced that the two mutation sites are highly conserved across a wide range of species, with the ability to alter different phosphorylation sites and destabilize the ASNS protein structure. The newly identified p.F123S mutation was predicted to be the most significantly destabilizing and detrimental mutation to the ASNS protein structure, compared to all other previously reported mutations.ConclusionEvidently, the presence of these compound heterozygous mutations could lead to severe clinical phenotypes and serve as a potential indicator for considerably higher risk with less optimistic prognosis in ASNSD patients.

Project description:Asparagine synthetase catalyses the transfer of an amino group from glutamine to aspartate to form glutamate and asparagine. The accumulation of free (nonprotein) asparagine in crops has implications for food safety because free asparagine is the precursor for acrylamide, a carcinogenic contaminant that forms during high-temperature cooking and processing. Here we review publicly available genome data for asparagine synthetase genes from species of the Pooideae subfamily, including bread wheat and related wheat species (Triticum and Aegilops spp.), barley (Hordeum vulgare) and rye (Secale cereale) of the Triticeae tribe. Also from the Pooideae subfamily: brachypodium (Brachypodium dIstachyon) of the Brachypodiae tribe. More diverse species are also included, comprising sorghum (Sorghum bicolor) and maize (Zea mays) of the Panicoideae subfamily and rice (Oryza sativa) of the Ehrhartoideae subfamily. The asparagine synthetase gene families of the Triticeae species each comprise five genes per genome, with the genes assigned to four groups: 1, 2, 3 (subdivided into 3.1 and 3.2) and 4. Each species has a single gene per genome in each group, except that some bread wheat varieties (genomes AABBDD) and emmer wheat (Triticum dicoccoides; genomes AABB) lack a group 2 gene in the B genome. This raises questions about the ancestry of cultivated pasta wheat and the B genome donor of bread wheat, suggesting that the hybridisation event that gave rise to hexaploid bread wheat occurred more than once. In phylogenetic analyses, genes from the other species cluster with the Triticeae genes, but brachypodium, sorghum and maize lack a group 2 gene, while rice has only two genes, one group 3 and one group 4. This means that TaASN2, the most highly expressed asparagine synthetase gene in wheat grain, has no equivalent in maize, rice, sorghum or brachypodium. An evolutionary pathway is proposed in which a series of gene duplications gave rise to the five genes found in modern Triticeae species.

Dataset Information

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

Publications

Novel Mutations in the Asparagine Synthetase Gene (<i>ASNS</i>) Associated With Microcephaly.

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