scholarly journals Mutation in ZDHHC15 Leads to Hypotonic Cerebral Palsy, Autism, Epilepsy, and Intellectual Disability

2021 ◽  
Vol 7 (4) ◽  
pp. e602
Author(s):  
Sara A. Lewis ◽  
Somayeh Bakhtiari ◽  
Jennifer Heim ◽  
Patricia Cornejo ◽  
James Liu ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Intellectual Disability ◽  
Protein Function ◽  
Motor Dysfunction ◽  
Facial Muscle ◽  
Loss Of Function ◽  
Functional Studies ◽  
Bona Fide ◽  
Muscle Hypotonia ◽  
Dental Crowding

ObjectiveTo determine whether mutations reported for ZDHHC15 can cause mixed neurodevelopmental disorders, we performed both functional studies on variant pathogenicity and ZDHHC15 function in animal models.MethodsWe examined protein function of 4 identified variants in ZDHHC15 in a yeast complementation assay and locomotor defects of loss-of-function genotypes in a Drosophila model.ResultsAlthough we assessed multiple patient variants, only 1 (p.H158R) affected protein function. We report a patient with a diagnosis of hypotonic cerebral palsy, autism, epilepsy, and intellectual disability associated with this bona fide damaging X-linked variant. Features include tall forehead with mild brachycephaly, down-slanting palpebral fissures, large ears, long face, facial muscle hypotonia, high-arched palate with dental crowding, and arachnodactyly. The patient had mild diminished cerebral volume, with left-sided T2/FLAIR hyperintense periatrial ovoid lesion. We found that loss-of-function mutations in orthologs of this gene cause flight and coordinated movement defects in Drosophila.ConclusionsOur findings support a functional expansion of this gene to a role in motor dysfunction. Although ZDHHC15 mutations represent a rare cause of neurodevelopmental disability, candidate variants need to be carefully assessed before pathogenicity can be determined.

scholarly journals Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

2021 ◽  
Author(s):  
Meena Balasubramanian ◽  
Alexander J. M. Dingemans ◽  
Shadi Albaba ◽  
Ruth Richardson ◽  
Thabo M. Yates ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Protein Function ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Mild Intellectual Disability ◽  
Related Disorder ◽  
Feeding Difficulties ◽  
Facial Phenotype ◽  
Novel Variants ◽  
Common Behaviour

AbstractWitteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10–12.

scholarly journals Biallelic loss-of-function variants inDOCK3cause muscle hypotonia, ataxia, and intellectual disability

2017 ◽  
Vol 92 (4) ◽  
pp. 430-433 ◽  
Author(s):  
K.L. Helbig ◽  
C. Mroske ◽  
D. Moorthy ◽  
S.A. Sajan ◽  
M. Velinov
Keyword(s):  
Intellectual Disability ◽  
Loss Of Function ◽  
Muscle Hypotonia

scholarly journals ATP7B Variant c.1934T>G p.Met645Arg Causes Wilson Disease by Promoting Exon 6 Skipping

2019 ◽  
Author(s):  
Daniele Merico ◽  
Carl Spickett ◽  
Matthew O’Hara ◽  
Boyko Kakaradov ◽  
Amit G. Deshwar ◽  
...  
Keyword(s):  
Liver Disease ◽  
Amino Acid ◽  
Wilson Disease ◽  
Protein Function ◽  
Amino Acid Change ◽  
Genetic Disorder ◽  
Molecular Diagnostic ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Functional Studies

ABSTRACTWilson Disease is a recessive genetic disorder caused by pathogenic loss-of-function variants in the ATP7B gene. It is characterized by disrupted copper homeostasis resulting in liver disease and/or neurological abnormalities. The variant NM_000053.3:c.1934T>G (Met645Arg) has been reported as compound heterozygous and is highly prevalent among Wilson Disease patients of Spanish descent. Accordingly, it is classified as pathogenic by leading molecular diagnostic centers. However, functional studies suggest that the amino acid change does not alter protein function, leading one ClinVar submitter to question its pathogenicity. Here we used a minigene system and gene-edited HepG2 cells to demonstrate that c.1934T>G causes approximately 70% skipping of exon 6. Exon 6 skipping results in frameshift and stop gain, which is expected to cause loss of ATP7B function. The elucidation of the mechanistic effect for this variant resolves any doubt about its pathogenicity and enables the development of genetic medicines for restoring correct splicing.

scholarly journals Accurate functional classification of thousands of BRCA1 variants with saturation genome editing

2018 ◽  
Author(s):  
Gregory M. Findlay ◽  
Riza M. Daza ◽  
Beth Martin ◽  
Melissa D. Zhang ◽  
Anh P. Leith ◽  
...  
Keyword(s):  
Genome Editing ◽  
Protein Function ◽  
Human Cell Line ◽  
Suppressor Gene ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Functional Studies ◽  
Transcript Stability ◽  
Uncertain Significance

AbstractVariants of uncertain significance (VUS) fundamentally limit the utility of genetic information in a clinical setting. The challenge of VUS is epitomized by BRCA1, a tumor suppressor gene integral to DNA repair and genomic stability. Germline BRCA1 loss-of-function (LOF) variants predispose women to early-onset breast and ovarian cancers. Although BRCA1 has been sequenced in millions of women, the risk associated with most newly observed variants cannot be definitively assigned. Data sharing attenuates this problem but it is unlikely to solve it, as most newly observed variants are exceedingly rare. In lieu of genetic evidence, experimental approaches can be used to functionally characterize VUS. However, to date, functional studies of BRCA1 VUS have been conducted in a post hoc, piecemeal fashion. Here we employ saturation genome editing to assay 96.5% of all possible single nucleotide variants (SNVs) in 13 exons that encode functionally critical domains of BRCA1. Our assay measures cellular fitness in a haploid human cell line whose survival is dependent on intact BRCA1 function. The resulting function scores for nearly 4,000 SNVs are bimodally distributed and almost perfectly concordant with established assessments of pathogenicity. Sequence-function maps enhanced by parallel measurements of variant effects on mRNA levels reveal mechanisms by which loss-of-function SNVs arise. Hundreds of missense SNVs critical for protein function are identified, as well as dozens of exonic and intronic SNVs that compromise BRCA1 function by disrupting splicing or transcript stability. We predict that these function scores will be directly useful for the clinical interpretation of cancer risk based on BRCA1 sequencing. Furthermore, we propose that this paradigm can be extended to overcome the challenge of VUS in other genes in which genetic variation is clinically actionable.

scholarly journals Identification of a New Mutation in RSK2, the Gene for Coffin–Lowry Syndrome (CLS), in Two Related Patients with Mild and Atypical Phenotypes

2021 ◽  
Vol 11 (8) ◽  
pp. 1105
Author(s):  
Mariateresa Di Stazio ◽  
Stefania Bigoni ◽  
Nicola Iuso ◽  
Josef Vuch ◽  
Rita Selvatici ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Kinase Activity ◽  
Genetic Variant ◽  
Loss Of Function ◽  
New Mutation ◽  
Diagnostic Features ◽  
S6 Kinase ◽  
Functional Studies ◽  
Ribosomal S6 Kinase ◽  
Generation Sequencing

Background: Coffin–Lowry syndrome (CLS) is a syndromic form of X-linked intellectual disability, in which specific associated facial, hand, and skeletal abnormalities are diagnostic features. Methods: In the present study, an unreported missense genetic variant of the ribosomal S6 kinase 2 (RSK2) gene has been identified, by next-generation sequencing, in two related males with two different phenotypes of intellectual disability (ID) and peculiar facial dysmorphisms. We performed functional studies on this variant and another one, already reported in the literature, involving the same amino acid residue but, to date, without an efficient characterization. Results: Our study demonstrated that the two variants involving residue 189 significantly impaired its kinase activity. Conclusions: We detected a loss-of-function RSK2 mutation with loss in kinase activity in a three-generation family with an X-linked ID.

scholarly journals The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Erna Davydova ◽  
Tadahiro Shimazu ◽  
Maren Kirstin Schuhmacher ◽  
Magnus E. Jakobsson ◽  
Hanneke L. D. M. Willemen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Function ◽  
Crucial Role ◽  
Complex I ◽  
Protein Modification ◽  
Zinc Binding ◽  
Functional Studies ◽  
Mitochondrial Respiratory Complex ◽  
Respiratory Complex I ◽  
Broad Specificity

AbstractPost-translational methylation plays a crucial role in regulating and optimizing protein function. Protein histidine methylation, occurring as the two isomers 1- and 3-methylhistidine (1MH and 3MH), was first reported five decades ago, but remains largely unexplored. Here we report that METTL9 is a broad-specificity methyltransferase that mediates the formation of the majority of 1MH present in mouse and human proteomes. METTL9-catalyzed methylation requires a His-x-His (HxH) motif, where “x” is preferably a small amino acid, allowing METTL9 to methylate a number of HxH-containing proteins, including the immunomodulatory protein S100A9 and the NDUFB3 subunit of mitochondrial respiratory Complex I. Notably, METTL9-mediated methylation enhances respiration via Complex I, and the presence of 1MH in an HxH-containing peptide reduced its zinc binding affinity. Our results establish METTL9-mediated 1MH as a pervasive protein modification, thus setting the stage for further functional studies on protein histidine methylation.

scholarly journals Biallelic ELMO3 mutations and loss of function for DOCK-mediated RAC1 activation result in intellectual disability

Small GTPases ◽  
2021 ◽  
pp. 1-8
Author(s):  
Viviane Tran ◽  
Marie-Anne Goyette ◽  
Mónica Martínez-García ◽  
Ana Jiménez de Domingo ◽  
Daniel Martín Fernández-Mayoralas ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Loss Of Function

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

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.

scholarly journals Partitioning of N-Ethylmaleimide-Sensitive Fusion (NSF) Protein Function in Drosophila melanogaster: dNSF1 Is Required in the Nervous System, and dNSF2 Is Required in Mesoderm

Genetics ◽  
2001 ◽  
Vol 158 (1) ◽  
pp. 265-278
Author(s):  
Jessica A Golby ◽  
Leigh Anna Tolar ◽  
Leo Pallanck
Keyword(s):  
Nervous System ◽  
Protein Function ◽  
Ectopic Expression ◽  
Drosophila Genome ◽  
Loss Of Function ◽  
Stage Of Development ◽  
Expression Studies ◽  
Larval Nervous System ◽  
Constitutive Secretion ◽  
Temporal And Spatial

Abstract The N-ethylmaleimide-sensitive fusion protein (NSF) promotes the fusion of secretory vesicles with target membranes in both regulated and constitutive secretion. While it is thought that a single NSF may perform this function in many eukaryotes, previous work has shown that the Drosophila genome contains two distinct NSF genes, dNSF1 and dNSF2, raising the possibility that each plays a specific secretory role. To explore this possibility, we generated mutations in the dNSF2 gene and used these and novel dNSF1 loss-of-function mutations to analyze the temporal and spatial requirements and the degree of functional redundancy between dNSF1 and dNSF2. Results of this analysis indicate that dNSF1 function is required in the nervous system beginning at the adult stage of development and that dNSF2 function is required in mesoderm beginning at the first instar larval stage of development. Additional evidence suggests that dNSF1 and dNSF2 may play redundant roles during embryonic development and in the larval nervous system. Ectopic expression studies demonstrate that the dNSF1 and dNSF2 gene products can functionally substitute for one another. These results indicate that the Drosophila NSF proteins exhibit similar functional properties, but have evolved distinct tissue-specific roles.

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