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Case Reports
. 2015 Jun;30(3):687-94.
doi: 10.1007/s11011-014-9618-0. Epub 2014 Sep 17.

Asparagine synthetase deficiency detected by whole exome sequencing causes congenital microcephaly, epileptic encephalopathy and psychomotor delay

Salma Ben-Salem  1 , Joseph G Gleeson, Aisha M Al-Shamsi, Barira Islam, Jozef Hertecant, Bassam R Ali, Lihadh Al-Gazali
Affiliations
Case Reports

Asparagine synthetase deficiency detected by whole exome sequencing causes congenital microcephaly, epileptic encephalopathy and psychomotor delay

Salma Ben-Salem et al. Metab Brain Dis. 2015 Jun.

Abstract

Deficiency of Asparagine Synthetase (ASNSD, MIM 615574) is a very rare autosomal recessive disorder presenting with some brain abnormalities. Affected individuals have congenital microcephaly and progressive encephalopathy associated with severe intellectual disability and intractable seizures. The loss of function of the asparagine synthetase (ASNS, EC 6.3.5.4), particularly in the brain, is the major cause of this particular congenital microcephaly. In this study, we clinically evaluated an affected child from a consanguineous Emirati family presenting with congenital microcephaly and epileptic encephalopathy. In addition, whole-exome sequencing revealed a novel homozygous substitution mutation (c.1193A > C) in the ASNS gene. This mutation resulted in the substitution of highly conserved tyrosine residue by cysteine (p.Y398C). Molecular modeling analysis predicts hypomorphic and damaging effects of this mutation on the protein structure and altering its enzymatic activity. Therefore, we conclude that the loss of ASNS function is most likely the cause of this condition in the studied family. This report brings the number of reported families with this very rare disorder to five and the number of pathogenic mutations in the ASNS gene to four. This finding extends the ASNS pathogenic mutations spectrum and highlights the utility of whole-exome sequencing in elucidation the causes of rare recessive disorders that are heterogeneous and/or overlap with other conditions.

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Conflict of interest statement

Conflict of interest

All authors have declared that no competing interests exist.

Figures

Fig. 1
Fig. 1
Pedigree and MRI pictures of a patient with asparagine synthetase deficiency. a. Pedigree showing one affected Emirati patient with asparagine synthetase deficiency. Circles and squares denote females and males respectively, filled symbols represent affected members, diagonal symbols indicate individuals with undesignated sex, double lines denote consanguineous marriage, Roman numbers indicate the generation number until their offspring, Arabic numbers depict participants in this study, star symbols represent the index patient. b to d. MRI pictures showing decreased cerebral volume and atrophy/hypoplasia. b. Midline sagittal with thin corpus callosum (arrows), reduced volume of pons (arrowhead), cerebellar hypoplasia and Blake’s pouch cyst (asterisk). c. Simplified gyral pattern (arrow), massive ventriculomegaly (asterisk, and cerebellar folia atrophy (arrowhead). d. Decreased cerebral volume and ventriculomegaly (asterisk). Arrow in 2D highlights that thalamus, which is relatively dark suggesting lack of edema
Fig. 2
Fig. 2
Schematic representation and molecular analysis of ASNS gene. a-(a to b) genomic organization of the ASNS gene. a to c. Protein representation of functional domain of the asparagine synthetase enzyme along with the corresponding position of all reported mutations. The identified mutation in this study is underlined b. Chromatograms of DNA sequence changes in the ASNS gene. A homozygous c.1193A>C mutation was identified in the affected child, which results in the substitution of p.Y398C. Both parents are carrier for this mutation. c. Schematic representation of amino acid sequence alignment of p.Y398C in different orthologues. c to a Alignment conversation was compiled using T-coffee online website (http://tcoffee.crg.cat/). C to b Logo was generated using WebLogo (weblogo.berkeley.edu) (Crooks et al. 2004). d. Humanized model of ASNS protein. a The cartoon representation shows that the protein is divided into distinct N-terminal domain (represented in yellow color) and C-terminal domain (represented in red color). The glutamine (represented as sticks in magenta color) is bound in N-terminal domain while AMP (represented as sticks in blue color) is bound in C-terminal domain. The cyan spheres represent the site for cation binding. b The protein consists of a long helix (represented in green color) which is distorted in the middle. Y398 (blue sticks) lies on this long helix and is at the interface of N-and C-terminal domain. R137 (blue sticks) lies in N-terminal domain and is within hydrogen bonding distance of Y398. c Representation of R137 and Y398 hydrogen bonding indicating that it is a key residue between the domain-domain interactions which contains the two active sites of the enzyme
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References

    1. Ai J, Tang Q, Wu Y, Xu Y, Feng T, Zhou R, Chen Y, Gao X, Zhu Q, Yue X, Pan Q, Xu S, Li J, Huang M, Daugherty-Holtrop J, He Y, Xu HE, Fan J, Ding J, Geng M. The role of polymeric immunoglobulin receptor in inflammation-induced tumor metastasis of human hepatocellular carcinoma. J Natl Cancer Inst. 2011;103:1696–1712. - PMC - PubMed
    1. Akawi NA, Al-Jasmi F, Al-Shamsi AM, Ali BR, Al-Gazali L. LINS, a modulator of the WNT signaling pathway, is involved in human cognition. Orphanet J Rare Dis. 2013;8:87. - PMC - PubMed
    1. Al-Gazali L, Ali BR. Mutations of a country: a mutation review of single gene disorders in the United Arab Emirates (UAE) Hum Mutat. 2010;31:505–520. - PubMed
    1. Andero R, Brothers SP, Jovanovic T, Chen YT, Salah-Uddin H, Cameron M, Bannister TD, Almli L, Stevens JS, Bradley B, Binder EB, Wahlestedt C, Ressler KJ. Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD. Sci Transl Med. 2013;5(188):188ra73. - PMC - PubMed
    1. Biesecker LG, Shianna KV, Mullikin JC. Exome sequencing: the expert view. Genome Biol. 2011;12:128. - PMC - PubMed

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