Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder

Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.

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Molecular characterisation of rare loss-of-function NPAS3 and NPAS4 variants identified in individuals with neurodevelopmental disorders

Scientific Reports ◽

10.1038/s41598-021-86041-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Joseph J. Rossi ◽

Jill A. Rosenfeld ◽

Katie M. Chan ◽

Haley Streff ◽

Victoria Nankivell ◽

...

Keyword(s):

Neurodevelopmental Disorders ◽

Protein Function ◽

Transcriptional Activity ◽

Neurodevelopmental Disorder ◽

Complete Loss ◽

Loss Of Function ◽

Targeted Disruption ◽

Clinical Exome Sequencing ◽

Partner Protein ◽

The Brain

AbstractAberrations in the excitatory/inhibitory balance within the brain have been associated with both intellectual disability (ID) and schizophrenia (SZ). The bHLH-PAS transcription factors NPAS3 and NPAS4 have been implicated in controlling the excitatory/inhibitory balance, and targeted disruption of either gene in mice results in a phenotype resembling ID and SZ. However, there are few human variants in NPAS3 and none in NPAS4 that have been associated with schizophrenia or neurodevelopmental disorders. From a clinical exome sequencing database we identified three NPAS3 variants and four NPAS4 variants that could potentially disrupt protein function in individuals with either developmental delay or ID. The transcriptional activity of the variants when partnered with either ARNT or ARNT2 was assessed by reporter gene activity and it was found that variants which truncated the NPAS3/4 protein resulted in a complete loss of transcriptional activity. The ability of loss-of-function variants to heterodimerise with neuronally enriched partner protein ARNT2 was then determined by co-immunoprecipitation experiments. It was determined that the mechanism for the observed loss of function was the inability of the truncated NPAS3/4 protein to heterodimerise with ARNT2. This further establishes NPAS3 and NPAS4 as candidate neurodevelopmental disorder genes.

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Bi-allelic Loss-of-Function Mutations in the NPR-C Receptor Result in Enhanced Growth and Connective Tissue Abnormalities

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2018.06.007 ◽

2018 ◽

Vol 103 (2) ◽

pp. 288-295 ◽

Cited By ~ 9

Author(s):

Eveline Boudin ◽

Tjeerd R. de Jong ◽

Tim C.R. Prickett ◽

Bruno Lapauw ◽

Kaatje Toye ◽

...

Keyword(s):

Connective Tissue ◽

Allelic Loss ◽

Loss Of Function ◽

Tissue Abnormalities

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Integrating de novo and inherited variants in over 42,607 autism cases identifies mutations in new moderate risk genes

10.1101/2021.10.08.21264256 ◽

2021 ◽

Author(s):

Xueya Zhou ◽

Pamela Feliciano ◽

Tianyun Wang ◽

Irina Astrovskaya ◽

Chang Shu ◽

...

Keyword(s):

Genetic Risk ◽

De Novo ◽

Meta Analysis ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Loss Of Function ◽

Moderate Risk ◽

Full Spectrum ◽

Risk Genes ◽

Biological Parents

AbstractDespite the known heritable nature of autism spectrum disorder (ASD), studies have primarily identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 19,843 cases with one or both biological parents and found that known ASD or neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of-function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive impairment compared to 129 ASD individuals with LoF variants in well-established, highly penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06). These findings will guide future gene discovery efforts and suggest that much larger numbers of ASD cases and controls are needed to identify additional genes that confer moderate risk of ASD through rare, inherited variants.

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Abstract PS2-25: Cell-free DNA based detection of mono-allelic versus bi-allelic loss of function for essential genes in breast cancer

10.1158/1538-7445.sabcs20-ps2-25 ◽

2021 ◽

Author(s):

Feng Xie ◽

Haoran Tang ◽

Yue Zhang ◽

Yong Huang

Keyword(s):

Breast Cancer ◽

Essential Genes ◽

Allelic Loss ◽

Loss Of Function ◽

Cell Free Dna ◽

Free Dna

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UBE3A-mediated PTPA ubiquitination and degradation regulate PP2A activity and dendritic spine morphology

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1820131116 ◽

2019 ◽

Vol 116 (25) ◽

pp. 12500-12505 ◽

Cited By ~ 7

Author(s):

Jie Wang ◽

Sen-Sen Lou ◽

Tingting Wang ◽

Rong-Jie Wu ◽

Guangying Li ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Dendritic Spine ◽

Isotope Labeling ◽

Neurodevelopmental Disorder ◽

Critical Role ◽

Motor Impairment ◽

Autism Spectrum ◽

Loss Of Function ◽

Pp2a Activity

Deficiency in the E3 ubiquitin ligase UBE3A leads to the neurodevelopmental disorder Angelman syndrome (AS), while additional dosage of UBE3A is linked to autism spectrum disorder. The mechanisms underlying the downstream effects of UBE3A gain or loss of function in these neurodevelopmental disorders are still not well understood, and effective treatments are lacking. Here, using stable-isotope labeling of amino acids in mammals and ubiquitination assays, we identify PTPA, an activator of protein phosphatase 2A (PP2A), as a bona fide ubiquitin ligase substrate of UBE3A. Maternal loss of Ube3a (Ube3am−/p+) increased PTPA level, promoted PP2A holoenzyme assembly, and elevated PP2A activity, while maternal 15q11–13 duplication containing Ube3a down-regulated PTPA level and lowered PP2A activity. Reducing PTPA level in vivo restored the defects in dendritic spine maturation in Ube3am−/p+ mice. Moreover, pharmacological inhibition of PP2A activity with the small molecule LB-100 alleviated both reduction in excitatory synaptic transmission and motor impairment in Ube3am−/p+ mice. Together, our results implicate a critical role of UBE3A-PTPA-PP2A signaling in the pathogenesis of UBE3A-related disorders and suggest that PP2A-based drugs could be potential therapeutic candidates for treatment of UBE3A-related disorders.

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A NOTCH3 homozygous nonsense mutation in familial Sneddon syndrome with pediatric stroke

Journal of Neurology ◽

10.1007/s00415-020-10081-5 ◽

2020 ◽

Author(s):

Elli Katharine Greisenegger ◽

Sara Llufriu ◽

Angel Chamorro ◽

Alvaro Cervera ◽

Adriano Jimenez-Escrig ◽

...

Keyword(s):

Nonsense Mutation ◽

Underlying Disease ◽

Allelic Loss ◽

Pediatric Stroke ◽

Loss Of Function ◽

Whole Exome ◽

Epidermal Growth ◽

Epidermal Growth Factor Repeat ◽

Homozygous Nonsense Mutation ◽

Sneddon Syndrome

Abstract Sneddon syndrome is a rare disorder affecting small and medium-sized blood vessels that is characterized by the association of livedo reticularis and stroke. We performed whole-exome sequencing (WES) in 2 affected siblings of a consanguineous family with childhood-onset stroke and identified a homozygous nonsense mutation within the epidermal growth factor repeat (EGFr) 19 of NOTCH3, p.(Arg735Ter). WES of 6 additional cases with adult-onset stroke revealed 2 patients carrying heterozygous loss-of-function variants in putative NOTCH3 downstream genes, ANGPTL4, and PALLD. Our findings suggest that impaired NOTCH3 signaling is one underlying disease mechanism and that bi-allelic loss-of-function mutation in NOTCH3 is a cause of familial Sneddon syndrome with pediatric stroke.

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Labour outcomes in siblings with channelopathy associated insensitivity to pain due to bi-alleleic SCN9A mutations

Obstetric Medicine ◽

10.1258/om.2012.110096 ◽

2012 ◽

Vol 5 (4) ◽

pp. 181-182 ◽

Cited By ~ 2

Author(s):

A Haestier ◽

S Hamilton ◽

R J Chilvers

Keyword(s):

Pelvic Fractures ◽

Sensory Loss ◽

Uneventful Recovery ◽

Allelic Loss ◽

Loss Of Function ◽

Case Histories ◽

Experienced Pain ◽

Caucasian Family ◽

Postpartum Outcomes ◽

Insensitivity To Pain

The gene SCN9A encodes for the voltage-gated sodium channel Nav1.7, which is highly expressed in pain sensing neurons. Bi-allelic ‘loss of function’ mutations result in a channelopathy associated with insensitivity to pain and anosmia. This is the first report of the labour and postpartum outcomes of two sisters who belong to a non-consanguineous Caucasian family with homozygous SCN9A mutations. Neither sister experienced pain during labour; this had major implications for the staff titrating the syntocinon for labour augmentation and contributed towards their ultimate delivery by caesarean section. During the postpartum period, one of the sisters developed lower limb sensory loss and investigations revealed a spinal haematoma and unrecognized bilateral pelvic fractures. The other sister had an uneventful recovery and both babies are well. These case histories underline the importance of pain in labour management and its function in alerting patients and staff to problems during the puerperium.

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Review for "A Novel Bi‐allelic Loss‐of‐Function Variant in MYOD1 : Further evidence for gene‐disease association and phenotypic variability in MYOD1 related myopathy"

10.1111/cge.13596/v2/review1 ◽

2019 ◽

Keyword(s):

Phenotypic Variability ◽

Disease Association ◽

Allelic Loss ◽

Loss Of Function

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