Early‑onset epilepsy and microcephaly‑capillary malformation syndrome caused by a novel STAMBP mutation in a Chinese boy

Wu, Fangrui; Dai, Ying; Wang, Juan; Cheng, Hui‐Ming; Wang, Yanqin; Li, Xiujuan; Pan, Yuan; Liao, Shuang; Jiang, Li; Chen, Jin; Yan, Lisi; Zhong, Min

doi:10.3892/mmr.2019.10757

Cited by 6 publications

(7 citation statements)

References 8 publications

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“…These patients have severe microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay, and multiple small capillary malformations on the skin. A variety of disease-causing mutations have been identified including frameshift, nonsense, splicing, and missense mutations, implicating loss-of-function as a mechanism of disease [146,[180][181][182][183]. Indeed, Amsh-deficient mice exhibit defects in cortical development similar to those in patients [39].…”

Section: Dysregulation Of Dubs Results In Developmental Diseasesmentioning

confidence: 99%

Deubiquitylases in developmental ubiquitin signaling and congenital diseases

2020

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Metazoan development from a one-cell zygote to a fully formed organism requires complex cellular differentiation and communication pathways. To coordinate these processes, embryos frequently encode signaling information with the small protein modifier ubiquitin, which is typically attached to lysine residues within substrates. During ubiquitin signaling, a three-step enzymatic cascade modifies specific substrates with topologically unique ubiquitin modifications, which mediate changes in the substrate’s stability, activity, localization, or interacting proteins. Ubiquitin signaling is critically regulated by deubiquitylases (DUBs), a class of ~100 human enzymes that oppose the conjugation of ubiquitin. DUBs control many essential cellular functions and various aspects of human physiology and development. Recent genetic studies have identified mutations in several DUBs that cause developmental disorders. Here we review principles controlling DUB activity and substrate recruitment that allow these enzymes to regulate ubiquitin signaling during development. We summarize key mechanisms of how DUBs control embryonic and postnatal differentiation processes, highlight developmental disorders that are caused by mutations in particular DUB members, and describe our current understanding of how these mutations disrupt development. Finally, we discuss how emerging tools from human disease genetics will enable the identification and study of novel congenital disease-causing DUBs.

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Section: Dysregulation Of Dubs Results In Developmental Diseasesmentioning

confidence: 99%

Deubiquitylases in developmental ubiquitin signaling and congenital diseases

2020

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“…At least 20 cases identified with STAMBP gene mutation have been reported ( McDonell et al, 2013 ; Pavlović et al, 2014 ; Faqeih et al, 2015 ; Naseer et al, 2016 ; Demikova et al, 2018 ; Hori et al, 2018 ; Lm, 2019 ; Wu et al, 2019 ). Global developmental delay, progressive microcephaly, epilepsy, and capillary malformations are the typical clinical manifestations.…”

Section: Discussionmentioning

confidence: 99%

“…Homozygous or compound heterozygous mutations in STAMBP have been reported to be pathogenic. Patients with microcephaly-capillary malformation syndrome (MICCAP: OMIM #614261) have biallelic mutations in the STAMBP gene ( McDonell et al, 2013 ; Pavlović et al, 2014 ; Faqeih et al, 2015 ; Naseer et al, 2016 ; Demikova et al, 2018 ; Hori et al, 2018 ; Lm, 2019 ; Wu et al, 2019 ). The phenotype of MICCAP consists of global developmental delay, progressive microcephaly, intractable epilepsy, and generalized capillary malformations on the skin.…”

Section: Introductionmentioning

confidence: 99%

Novel compound heterozygous mutation in STAMBP causes a neurodevelopmental disorder by disrupting cortical proliferation

Li²,

Huang³

et al. 2022

Front. Neurosci.

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BackgroundMutations in the STAMBP gene, which encodes a deubiquitinating isopeptidase called STAM-binding protein, are related to global developmental delay, microcephaly, and capillary malformation. Owing to the limited number of reported cases, the functional and phenotypic characteristics of STAMBP variants require further elucidation.Materials and methodsWhole exome sequencing was performed on a patient presenting with a neurodevelopmental disorder. Novel compound heterozygous mutations in STAMBP [c.843_844del (p.C282Wfs*11) and c.920G > A (p.G307E)] were identified and validated using Sanger sequencing. A 3D human cortical organoid model was used to investigate the function of STAMBP and the pathogenicity of the novel mutation (c.920G > A, p.G307E).ResultsThe patient was presented with global developmental delay, autism spectrum disorder, microcephaly, epilepsy, and dysmorphic facial features but without apparent capillary malformation on the skin and organs. Cortical organoids with STAMBP knockout (KO) showed significantly lower proliferation of neural stem cells (NSCs), leading to smaller organoids that are characteristic of microcephaly. Furthermore, STAMBP disruption did not affect apoptosis in early cortical organoids. After re-expressing wild-type STAMBP, STAMBPG307E, and STAMBPT313I (a known pathogenic mutation) within STAMBP KO organoids, only STAMBPWT rescued the impaired proliferation of STAMBP deficient organoids, but not STAMBPG307E and STAMBPT313I.ConclusionOur findings demonstrate that the clinical phenotype of STAMBP mutations is highly variable, and patients with different STAMBP mutations show differences in the severity of symptoms. The STAMBP missense mutation identified here is a novel pathogenic mutation that impairs the proliferation of NSCs in human brain development.

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“…MIC-CAP has been reported in 18 individuals from 16 families to date (Carter et al, 2011;Demikova et al, 2018;Faqeih et al, 2015;Hori et al, 2018;Isidor et al, 2011;McDonell et al, 2013;Mirzaa et al, 2011;Naseer et al, 2016;Pavlovi c et al, 2014;Sсhugareva & Shumeeva, 2019;Wu et al, 2019). There is no literature describing the natural history or long-term outcomes of these patients.…”

Section: Introductionmentioning

confidence: 99%

Further clinical delineation of microcephaly‐capillary malformation syndrome

Postma

Zambonin

Khouj

et al. 2022

American J of Med Genetics Pt A

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Microcephaly-Capillary Malformation syndrome (MIC-CAP) is a rare genetic disorder reported in 18 individuals to date. The clinical features typically include microcephaly, multiple cutaneous capillary malformations, seizures, neurologic impairment, and global developmental delay. Currently, there is little published information about the natural history and long-term outcomes for individuals with MIC-CAP. In this report, we provide follow up on two previously published patients and describe four new patients. The included patients highlight increased variability in the clinical spectrum and provide novel information regarding medical complications and recurrent variants.

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Early‑onset epilepsy and microcephaly‑capillary malformation syndrome caused by a novel STAMBP mutation in a Chinese boy

Cited by 6 publications

References 8 publications

Deubiquitylases in developmental ubiquitin signaling and congenital diseases

Deubiquitylases in developmental ubiquitin signaling and congenital diseases

Novel compound heterozygous mutation in STAMBP causes a neurodevelopmental disorder by disrupting cortical proliferation

Further clinical delineation of microcephaly‐capillary malformation syndrome

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