0000000000187709

AUTHOR

Shehla Mohammed

showing 3 related works from this author

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

2021

AbstractWhereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene,SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carryingSATB1variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression…

0301 basic medicineMaleModels MolecularMISSENSE MUTATIONSCHROMATINTranscription GeneticCellMedizinDiseaseHaploinsufficiencymedicine.disease_cause0302 clinical medicineMissense mutationde novo variantsGenetics (clinical)INTERLEUKIN-2seizuresGenetics0303 health sciencesMutationChromatin bindingneurodevelopmental disordersMetabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6]SATB1Phenotypemedicine.anatomical_structureintellectual disabilityFemaleHaploinsufficiencyteeth abnormalitiesProtein BindingNeuroinformaticsEXPRESSIONGENESMutation MissenseBiologyBINDING PROTEINREGION03 medical and health sciencesSATB1Protein DomainsReportGeneticsmedicineHPO-based analysisHumansGenetic Association StudiesHpo-based Analysis ; Satb1 ; Cell-based Functional Assays ; De Novo Variants ; Intellectual Disability ; Neurodevelopmental Disorders ; Seizures ; Teeth Abnormalities030304 developmental biology[SDV.GEN]Life Sciences [q-bio]/GeneticsNeurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]Matrix Attachment Region Binding Proteins030104 developmental biologyNeurodevelopmental DisordersMutationNanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]030217 neurology & neurosurgerycell-based functional assays
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Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy

2013

Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle a…

BiopsyVesicular Transport ProteinsAutophagy-Related ProteinsGenes RecessiveConsanguinityBiologymedicine.disease_causeArticleCataract03 medical and health sciencesConsanguinity0302 clinical medicineCataractsAntigens NeoplasmGeneticsmedicineAutophagyHumansVici syndromeExomeFamilyMuscle SkeletalExomeImmunodeficiency030304 developmental biologyGenetics0303 health sciencesMutationAutophagyIntracellular Signaling Peptides and ProteinsLysosome-Associated Membrane GlycoproteinsProteinsmedicine.diseaseMutationAutophagy Protein 5Agenesis of Corpus CallosumLysosomes030217 neurology & neurosurgeryNature genetics
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Missense variants in TAF1 and developmental phenotypes: Challenges of determining pathogenicity

2019

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity…

Genetics0303 health sciencesHeart malformation030305 genetics & heredityBiologymedicine.diseaseArticleHypotonia03 medical and health sciencesAutism spectrum disorderHuman Phenotype OntologyIntellectual disabilityGeneticsmedicineCopy-number variationAllelemedicine.symptomGenetics (clinical)Exome sequencing030304 developmental biologyHuman Mutation
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