Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort

Alharby, Essa; Faqeih, Eissa; Saleh, Mohammed; Alameer, Seham; Almuntashri, Makki; Pastore, Annalisa; Samman, Manar; Alnawfal, Abdullah M; Hashem, Mais; Zaytuni, Dimah; Alharbi, Ghadeer; Almannai, Mohammed; Alasmari, Ali; Mahmoud, Adel A.; Alwadei, Ali H; Jad, Lamya; Al-Otaibi, Ali; Al-Hakami, Fahad; Eyaid, Wafaa; Alkuraya, Fowzan S.; Alfadhel, Majid; Peake, Roy W A; Almontashiri, Naif A M

doi:10.1038/s41436-020-0919-x

Cited by 9 publications

(6 citation statements)

References 23 publications

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“…12 To date, about 75 ASNSD patients in 55 distinct families have been described. 10,[12][13][14][15][16][17][18][19][20][21] Case reports have commonly described newborns with congenital microcephaly, simplified gyral pattern, axial hypotonia, appendicular spasticity, early onset seizures, and progressive brain atrophy, often leading to premature mortality. Suspicion of ASNSD is typically prompted by recognition of the phenotype in newborns and subsequently confirmed by whole-exome DNA sequencing that identified mutations in the ASNS gene.…”

Section: Introductionmentioning

confidence: 99%

“…The first report of Asn synthetase deficiency (ASNSD) described four families with mutations in the ASNS gene 12 . To date, about 75 ASNSD patients in 55 distinct families have been described 10,12–21 . Case reports have commonly described newborns with congenital microcephaly, simplified gyral pattern, axial hypotonia, appendicular spasticity, early onset seizures, and progressive brain atrophy, often leading to premature mortality.…”

Section: Introductionmentioning

confidence: 99%

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Characterizing asparagine synthetase deficiency variants in lymphoblastoid cell lines

et al. 2023

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Asparagine synthetase (ASNS) catalyzes the synthesis of asparagine (Asn) from aspartate and glutamine. Biallelic mutations in the ASNS gene result in ASNS Deficiency (ASNSD). Children with ASNSD exhibit congenital microcephaly, epileptic‐like seizures, and continued brain atrophy, often leading to premature mortality. This report describes a 4‐year‐old male with global developmental delay and seizures with two novel mutations in the ASNS gene, c.614A > C (maternal) and c.1192dupT (paternal) encoding p.H205P and p.Y398Lfs*4 variants, respectively. We employed the novel use of immortalized lymphoblastoid cell lines (LCL) to show that the proliferation of the heterozygotic parental LCL was not severely affected by culture in Asn‐free medium, but growth of the child's cells was suppressed by about 50%. Asn production by the LCL from both the father and the child was significantly decreased relative to the mother's cells. mRNA and protein analysis of the paternal LCL cells for the Y398Lfs*4 variant revealed reductions in both. Attempts to ectopically express the truncated Y398Lfs*4 variant in either HEK293T or ASNS‐null cells resulted in little or no detectable protein. Expression and purification of the H205P variant from HEK293T cells revealed enzymatic activity similar to wild‐type ASNS. Stable expression of WT ASNS rescued the growth of ASNS‐null JRS cells in Asn‐free medium and the H205P variant was only slightly less effective. However, the Y398Lfs*4 variant appeared to be unstable in JRS cells. These results indicate that co‐expression of the H205P and Y398Lfs*4 variants leads to a significant reduction in Asn synthesis and cellular growth.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterizing asparagine synthetase deficiency variants in lymphoblastoid cell lines

et al. 2023

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“…The affected children shared the features of severe encephalopathy, congenital microcephaly, progressive brain atrophy, early onset seizures, axial hypotonia, severe appendicular spasticity, and often, mortality at a premature age (reviewed in ( 6 , 11 , 12 )). Since the initial report, about 50 independent ASNS protein variants have been identified (summarized by ( 13 , 14 , 15 )). The exact mechanisms that cause the overt symptoms of the disease are not well understood, and at present, the disease can only be diagnosed through DNA sequencing.…”

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confidence: 99%

Cellular and molecular characterization of two novel asparagine synthetase gene mutations linked to asparagine synthetase deficiency

Staklinski

Chang²,

Yu³

et al. 2022

Journal of Biological Chemistry

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“…About 70%, 55%, and 40% of patients had hyperreflexia, axial hypotonia, and visual impairment, respectively. MRI findings showed that near to 100% of the patients had brain atrophy, and 75%, 62%, and 61% of patients reported to have delayed myelination, a gyral simplification pattern, and a decreased size of the pons, respectively (Abdel‐Salam & Abdel‐Hamid, 2021 ; Abhyankar et al., 2017 ; Akesson et al., 2020 ; Alfadhel et al., 2015 ; Alharby et al., 2020 ; Altıntaş et al., 2023 ; Ben‐Salem et al., 2015 ; Chen et al., 2019 ; Churchill et al., 2020 ; Faoucher et al., 2019 ; Galada et al., 2018 ; Gataullina et al., 2016 ; Gupta et al., 2017 ; Liu et al., 2022 ; Monies et al., 2019 ; Palmer et al., 2015 ; Radha Rama Devi & Naushad, 2019 ; Reed, 2016 ; Ruzzo et al., 2013 ; Sacharow et al., 2018 ; Saini et al., 2023 ; Schleinitz et al., 2018 ; Seidahmed et al., 2016 ; Shaheen et al., 2019 ; Sprute et al., 2019 ; Staklinski et al., 2022 , 2023 ; Sun et al., 2017 ; Wang et al., 2020 ; Yamamoto et al., 2017 ; Yingjun et al., 2019 ; Zhu et al., 2023 ).…”

Section: Discussionmentioning

confidence: 99%

A novel variant in ASNS gene responsible for syndromic intellectual disability and microcephaly: Case report and literature review

Jahanpanah,

Mokhtari,

Mokaber

et al. 2024

Molec Gen & Gen Med

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BackgroundThe ASNS (ASNS, MIM 108370) gene variations are responsible for asparagine synthetase deficiency (ASNSD, MIM 615574), a very rare autosomal recessive disease characterized by cerebral anomalies. These patients have congenital microcephaly, progressive encephalopathy, severe intellectual disability, and intractable seizures.MethodClinical characteristics of the patient were collected. Exome sequencing was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. The structure of the protein was checked using the DynaMut2 web server.ResultsThe proband is an 11‐year‐old Iranian‐Azeri girl with primary microcephaly and severe intellectual disability in a family with a consanguineous marriage. Symptoms emerged around the 10–20th days of life, when refractory epileptic gaze and unilateral tonic–clonic seizures initiated without any provoking factor such as fever. A brain MRI revealed no abnormalities except for brain atrophy. The karyotype was normal. Using exome sequencing, we identified a novel homozygous variant of thymine to adenine (NM_001673.5:c.538T>A) in the ASNS gene. Both parents had a heterozygous variant in this location. Subsequently, Sanger sequencing confirmed this variant. We also reviewed the clinical manifestations and MRI findings of the previously reported patients.ConclusionIn the present study, a novel homozygous variant was recognized in the ASNS gene in an Iranian‐Azeri girl manifesting typical ASNSD symptoms, particularly intellectual disability and microcephaly. This study expands the mutation spectrum of ASNSD and reviews previously reported patients.

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Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort

Cited by 9 publications

References 23 publications

Characterizing asparagine synthetase deficiency variants in lymphoblastoid cell lines

Characterizing asparagine synthetase deficiency variants in lymphoblastoid cell lines

Cellular and molecular characterization of two novel asparagine synthetase gene mutations linked to asparagine synthetase deficiency

A novel variant in ASNS gene responsible for syndromic intellectual disability and microcephaly: Case report and literature review

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