Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

Alkhateeb, Asem; Aburahma, Samah K.; Habbab, Wesal; Thompson, Iain

doi:10.1007/s11011-016-9827-9

Cited by 20 publications

(14 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Including the two patients we report here, 29 patients with RARS2 mutations are described in literature so far (Namavar et al 2011a;Cassandrini et al 2013;Rankin et al 2010;Glamuzina et al 2012;Kastrissianakis et al 2013;Joseph et al 2014;Li et al 2015;Lax et al 2015;Nishri et al 2016;Ngoh et al 2016;Alkhateeb et al 2016). Splice site, nonsense, or missense mutations are identified throughout the RARS2 gene, but no patients with biallelic null mutations were identified, supporting the assumption that complete abolishment of tRNA-arg would be lethal.…”

Section: Discussionsupporting

confidence: 65%

See 1 more Smart Citation

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

et al. 2016

View full text Add to dashboard Cite

Mutations in the mitochondrial arginyl tRNA synthetase (RARS2) gene are associated with Pontocerebellar Hypoplasia type 6 (PCH6). Here we report two patients, compound heterozygous for RARS2 mutations, presenting with early onset epileptic encephalopathy and (progressive) atrophy of both supra-and infratentorial structures. Early pontocerebellar hypoplasia was virtually absent and respiratory chain (RC) defects could not be detected in muscle biopsies. Both patients carried a novel missense mutation c.1544A>G (p.(Asp515Gly)) in combination with either a splice site (c.297+2T>G) or a frameshift (c.452_454insC) mutation. The splice site mutation induced skipping of exon 4.These two patients expand the phenotypical spectrum associated with RARS2 mutations beyond the first report of PCH6 by Edvardson and colleagues. We propose to classify RARS2-associated phenotypes as an early onset mitochondrial encephalopathy, since this is more in agreement with both clinical presentation and underlying genetic cause.

show abstract

Section: Discussionsupporting

confidence: 65%

“…Unfortunately, little additional information regarding the clinical follow-up or age of brain MRI was provided (Alkhateeb et al 2016). …”

Section: Discussionmentioning

confidence: 99%

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Notably, null mutations of WWOX/Wwox gene in humans and animals lead to severe neural diseases (e.g., microcephaly, seizure, ataxia, etc. ), growth retardation, metabolic disorders, developmental delay, and early death (Aldaz et al, 2014; Chang et al, 2014; Alkhateeb et al, 2016; Elsaadany et al, 2016). Nevertheless, no spontaneous cancer formation has been seen in the newborns, arguing whether WWOX is a real tumor suppressor.…”

Section: Tumor Suppressor Wwox Is Anchored On the Cell Membrane By Hymentioning

confidence: 99%

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

Hsu

Chiang

Sze

et al. 2016

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Hyaluronidase HYAL-2 is a membrane-anchored protein and also localizes, in part, in the lysosome. Recent study from animal models revealed that both HYAL-1 and HYAL-2 are essential for the metabolism of hyaluronan (HA). Hyal-2 deficiency is associated with chronic thrombotic microangiopathy with hemolytic anemia in mice due to over accumulation of high molecular size HA. HYAL-2 is essential for platelet generation. Membrane HYAL-2 degrades HA bound by co-receptor CD44. Also, in a non-canonical signal pathway, HYAL-2 serves as a receptor for transforming growth factor beta (TGF-β) to signal with downstream tumor suppressors WWOX and SMAD4 to control gene transcription. When SMAD4 responsive element is overly driven by the HYAL-2–WWOX–SMAD4 signaling complex, cell death occurs. When rats are subjected to traumatic brain injury, over accumulation of a HYAL-2–WWOX complex occurs in the nucleus to cause neuronal death. HA induces the signaling of HYAL-2–WWOX–SMAD4 and relocation of the signaling complex to the nucleus. If the signaling complex is overexpressed, bubbling cell death occurs in WWOX-expressing cells. In addition, a small synthetic peptide Zfra (zinc finger-like protein that regulates apoptosis) binds membrane HYAL-2 of non-T/non-B spleen HYAL-2+ CD3− CD19− Z lymphocytes and activates the cells to generate memory anticancer response against many types of cancer cells in vivo. Whether the HYAL-2–WWOX–SMAD4 signaling complex is involved is discussed. In this review and opinion article, we have updated the current knowledge of HA, HYAL-2 and WWOX, HYAL-2–WWOX–SMAD4 signaling, bubbling cell death, and Z cell activation for memory anticancer response.

show abstract

“…As an example, in Jordan only a limited number of families with children with NDDs underwent extensive molecular testing in a research context leaving the majority of patients without a firm diagnosis. [5][6][7][8][9][10][11][12][13] This study aims to establish whole exome sequencing (WES) as first-tier diagnostics in undiagnosed neurodevelopmental cases in Jordan.…”

Section: Introductionmentioning

confidence: 99%

Genetic basis of neurodevelopmental disorders in 103 Jordanian families

et al. 2020

View full text Add to dashboard Cite

We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in‐house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease‐causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability.

show abstract

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

Cited by 20 publications

References 47 publications

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy?

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

Genetic basis of neurodevelopmental disorders in 103 Jordanian families

Contact Info

Product

Resources

About