Molecular analyses in Indonesian individuals with intellectual disability and microcephaly

Background Intellectual disability (ID) often coincides with anabnormal head circumference (HC). Since the HC is a reflectionof brain size, abnormalities in HC may be a sign of a brain anomaly.Although microcephaly is often secondary to ID, hereditary(autosomal recessive) forms of primary microcephaly (MCPH)exist that result in ID.Objective To investigate mutations in MCPH genes in patientswith ID and microcephaly.Methods From a population of 527 Indonesian individuals withID, 48 patients with microcephaly (9.1 %) were selected. Thesepatients were previously found to be normal upon conventionalkaryotyping, fragile X mental retardation 1 (FMRl) gene analysis,subtelomeric deletion, and duplication multiplex ligationdependentprobe amplification (MLPA). Sanger sequencing forabnormal spindle-like microcephaly-associated (ASPM) and WDrepeat domain 62 (WDR62) was performed in all 48 subjects, whilesequencing for microcephalin (MCPHl), cyclin-dependent kinase5 (CDK5) regulatory subunit-associated protein 2 (CD5KRAP2) ,centromere protein} (CENPJ), and SCUfALl interrupting locus(STIL) was conducted in only the subjects with an orbitofrontalcortex (OFC) below -4 SD.Results In all genes investigated, 66 single nucleotide polymorphisms(SNPs) and 15 unclassified variants which were predictedas unlikely to be pathogenic (lN2), were identified. Possiblepathogenic variants (lN3) were identified in ASPM. However,since none of the patients harboured compound heterozygouslikely pathogenic mutations, no molecular MCPH diagnosis couldbe established. Interestingly, one of the patients harboured thesame variants as her unaffected monozygotic twin sister, indicatingthat our cohort included a discordant twin.Conclusions This study is the first to investigate for possible geneticcauses ofMCPH in the Indonesian population. The absenceof causative pathogenic mutations in the MCPH genes tested may originate from several factors. The identification of UV2and UV3 variants as well as the absence of causative pathogenicmutations calls for further investigations.

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Recent selection of candidate genes for mammal domestication in Europeans and language change in Europe: a hypothesis

10.1101/684621 ◽

2019 ◽

Cited By ~ 1

Author(s):

Antonio Benítez-Burraco ◽

Evgeny Chekalin ◽

Sergey Bruskin ◽

Irina Morozova

Keyword(s):

Bronze Age ◽

Language Change ◽

Brain Size ◽

Human Cognition ◽

Nucleotide Polymorphisms ◽

Late Neolithic ◽

Single Nucleotide ◽

Genome Data ◽

And Function ◽

And Behavior

AbstractHuman evolution resulted from changes in our biology, behavior, and culture. One source of these changes has been hypothesized to be our self-domestication (that is, the development in humans of features commonly found in domesticated strains of mammals, seemingly as a result of selection for reduced aggression). Signals of domestication, notably brain size reduction, have increased in recent times. In this paper we compare whole-genome data between Late Neolithic/Bronze Age individuals and modern Europeans and show that genes associated with mammal domestication and with neural crest development and function are significantly differently enriched in nonsynonymous single nucleotide polymorphisms between these two groups. We hypothesize how these changes might account for the increased features of self-domestication in modern humans and ultimately, for subtle recent changes in human cognition and behavior, including language.

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Biallelic variants in PSMB1 encoding the proteasome subunit β6 cause impairment of proteasome function, microcephaly, intellectual disability, developmental delay and short stature

Human Molecular Genetics ◽

10.1093/hmg/ddaa032 ◽

2020 ◽

Vol 29 (7) ◽

pp. 1132-1143 ◽

Cited By ~ 2

Author(s):

Muhammad Ansar ◽

Frédéric Ebstein ◽

Hayriye Özkoç ◽

Sohail A Paracha ◽

Justyna Iwaszkiewicz ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Autosomal Recessive ◽

Brain Size ◽

Autosomal Recessive Disorders ◽

Proteasome Subunit ◽

Pathogenic Variants ◽

The Family ◽

Proteasome Subunits ◽

Recessive Disorders

Abstract The molecular cause of the majority of rare autosomal recessive disorders remains unknown. Consanguinity due to extensive homozygosity unravels many recessive phenotypes and facilitates the detection of novel gene-disease links. Here, we report two siblings with phenotypic signs, including intellectual disability (ID), developmental delay and microcephaly from a Pakistani consanguineous family in which we have identified homozygosity for p(Tyr103His) in the PSMB1 gene (Genbank NM_002793) that segregated with the disease phenotype. PSMB1 encodes a β-type proteasome subunit (i.e. β6). Modeling of the p(Tyr103His) variant indicates that this variant weakens the interactions between PSMB1/β6 and PSMA5/α5 proteasome subunits and thus destabilizes the 20S proteasome complex. Biochemical experiments in human SHSY5Y cells revealed that the p(Tyr103His) variant affects both the processing of PSMB1/β6 and its incorporation into proteasome, thus impairing proteasome activity. CRISPR/Cas9 mutagenesis or morpholino knock-down of the single psmb1 zebrafish orthologue resulted in microcephaly, microphthalmia and reduced brain size. Genetic evidence in the family and functional experiments in human cells and zebrafish indicates that PSMB1/β6 pathogenic variants are the cause of a recessive disease with ID, microcephaly and developmental delay due to abnormal proteasome assembly.

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Single-nucleotide polymorphisms in uncoding regions of ALS2 gene of Japanese patients with autosomal-recessive amyotrophic lateral sclerosis

Neurological Research ◽

10.1179/016164103101201733 ◽

2003 ◽

Vol 25 (5) ◽

pp. 505-509 ◽

Cited By ~ 4

Author(s):

Isao Nagano ◽

Tetsuro Murakami ◽

Mito Shiote ◽

Yasuhiro Manabe ◽

Shinji Hadano ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Single Nucleotide Polymorphisms ◽

Autosomal Recessive ◽

Japanese Patients ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Lateral Sclerosis

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Progranulin Levels in Plasma and Cerebrospinal Fluid in Granulin Mutation Carriers

Dementia and Geriatric Cognitive Disorders Extra ◽

10.1159/000447738 ◽

2016 ◽

Vol 6 (2) ◽

pp. 330-340 ◽

Cited By ~ 26

Author(s):

Lieke H.H. Meeter ◽

Holger Patzke ◽

Gordon Loewen ◽

Elise G.P. Dopper ◽

Yolande A.L. Pijnenburg ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Single Nucleotide Polymorphisms ◽

Frontotemporal Dementia ◽

Coefficient Of Variation ◽

Treatment Monitoring ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Therapeutic Trials ◽

Mutation Carriers ◽

Pathogenic Mutations

Background: Pathogenic mutations in the granulin gene (GRN) are causative in 5-10% of patients with frontotemporal dementia (FTD), mostly leading to reduced progranulin protein (PGRN) levels. Upcoming therapeutic trials focus on enhancing PGRN levels. Methods: Fluctuations in plasma PGRN (n = 41) and its relationship with cerebrospinal fluid (CSF, n = 32) and specific single nucleotide polymorphisms were investigated in pre- and symptomatic GRN mutation carriers and controls. Results: Plasma PGRN levels were lower in carriers than in controls and showed a mean coefficient of variation of 5.3% in carriers over 1 week. Although plasma PGRN correlated with CSF PGRN in carriers (r = 0.54, p = 0.02), plasma only explained 29% of the variability in CSF PGRN. rs5848, rs646776 and rs1990622 genotypes only partly explained the variability of PGRN levels between subjects. Conclusions: Plasma PGRN is relatively stable over 1 week and therefore seems suitable for treatment monitoring of PGRN-enhancing agents. Since plasma PGRN only moderately correlated with CSF PGRN, CSF sampling will additionally be needed in therapeutic trials.

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Panel-based NGS Reveals Novel Pathogenic Mutations in Autosomal Recessive Retinitis Pigmentosa

Scientific Reports ◽

10.1038/srep19531 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 27

Author(s):

Raquel Perez-Carro ◽

Marta Corton ◽

Iker Sánchez-Navarro ◽

Olga Zurita ◽

Noelia Sanchez-Bolivar ◽

...

Keyword(s):

Retinitis Pigmentosa ◽

Autosomal Recessive ◽

Copy Number Variations ◽

Single Nucleotide ◽

Targeted Next Generation Sequencing ◽

Large Deletions ◽

Retinal Dystrophies ◽

Pathogenic Mutations ◽

Detection Of Mutations ◽

Next Generation Sequencing Ngs

Abstract Retinitis pigmentosa (RP) is a group of inherited progressive retinal dystrophies (RD) characterized by photoreceptor degeneration. RP is highly heterogeneous both clinically and genetically, which complicates the identification of causative genes and mutations. Targeted next-generation sequencing (NGS) has been demonstrated to be an effective strategy for the detection of mutations in RP. In our study, an in-house gene panel comprising 75 known RP genes was used to analyze a cohort of 47 unrelated Spanish families pre-classified as autosomal recessive or isolated RP. Disease-causing mutations were found in 27 out of 47 cases achieving a mutation detection rate of 57.4%. In total, 33 pathogenic mutations were identified, 20 of which were novel mutations (60.6%). Furthermore, not only single nucleotide variations but also copy-number variations, including three large deletions in the USH2A and EYS genes, were identified. Finally seven out of 27 families, displaying mutations in the ABCA4, RP1, RP2 and USH2A genes, could be genetically or clinically reclassified. These results demonstrate the potential of our panel-based NGS strategy in RP diagnosis.

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Single Nucleotide Polymorphisms of theGJB2andGJB6Genes Are Associated with Autosomal Recessive Nonsyndromic Hearing Loss

BioMed Research International ◽

10.1155/2015/318727 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Ana Paula Grillo ◽

Flávia Marcorin de Oliveira ◽

Gabriela Queila de Carvalho ◽

Ruan Felipe Vieira Medrano ◽

Sueli Matilde da Silva-Costa ◽

...

Keyword(s):

Hearing Loss ◽

Single Nucleotide Polymorphisms ◽

Autosomal Recessive ◽

Nucleotide Polymorphisms ◽

Nonsyndromic Hearing Loss ◽

Single Nucleotide ◽

Specific Pcr ◽

Sequence Variations ◽

Allele Specific ◽

Allele Specific Pcr

Single nucleotide polymorphisms (SNPs) are important markers in many studies that link DNA sequence variations to phenotypic changes; such studies are expected to advance the understanding of human physiology and elucidate the molecular basis of diseases. TheDFNB1locus, which contains theGJB2andGJB6genes, plays a key role in nonsyndromic hearing loss. Previous studies have identified important mutations in this locus, but the contribution of SNPs in the genes has not yet been much investigated. The aim of this study was to investigate the association of nine polymorphisms located within theDFNB1locus with the occurrence of autosomal recessive nonsyndromic hearing loss (ARNSHL). The SNPs rs3751385 (C/T), rs7994748 (C/T), rs7329857 (C/T), rs7987302 (G/A), rs7322538 (G/A), rs9315400 (C/T), rs877098 (C/T), rs945369 (A/C), and rs7333214 (T/G) were genotyped in 122 deaf patients and 132 healthy controls using allele-specific PCR. There were statistically significant differences between patients and controls, in terms of allelic frequencies in the SNPs rs3751385, rs7994748, rs7329857, rs7987302, rs945369, and rs7333214 (P<0.05). No significant differences between the two groups were observed for rs7322538, rs9315400, and rs877098. Our results suggest that SNPs present in theGJB2andGJB6genes may have an influence on ARNSHL in humans.

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Novel frameshift variant (c.409dupG) in SLC25A38 is a common cause of congenital sideroblastic anaemia in the Indian subcontinent

Journal of Clinical Pathology ◽

10.1136/jclinpath-2020-206647 ◽

2020 ◽

pp. jclinpath-2020-206647

Author(s):

Niveditha Ravindra ◽

Rekha Athiyarath ◽

Eswari S ◽

Sumithra S ◽

Uday Kulkarni ◽

...

Keyword(s):

Autosomal Recessive ◽

Indian Subcontinent ◽

Nucleotide Polymorphisms ◽

Rare Disorders ◽

Phenotype Correlation ◽

Single Nucleotide ◽

Pathogenic Variants ◽

Sideroblastic Anaemia ◽

Ring Sideroblasts ◽

Quantify Gene Expression

AimsCongenital sideroblastic anaemias (CSAs) are a group of rare disorders with the presence of ring sideroblasts in the bone marrow. Pathogenic variants are inherited in an autosomal recessive/X-linked fashion. The study was aimed at characterising the spectrum of mutations in SLC25A38 and ALAS2 genes in sideroblastic anaemia patients, exploring the genotype-phenotype correlation and identifying the haplotype associated with any recurrent mutation.Patients and methodsTwenty probable CSA patients were retrospectively analysed for genetic variants in ALAS2 and SLC25A38 genes by direct bidirectional sequencing. Real-time PCR was used to quantify gene expression in a case with promoter region variant in ALAS2. Three single nucleotide polymorphisms were used to establish the haplotype associated with a recurrent variant in the SLC25A38 gene.ResultsSix patients had causative variants in ALAS2 (30%) and 11 had variants in SLC25A38 (55%). The ALAS2 mutated cases presented at a significantly later age than the SLC25A38 cases. A frameshift variant in SLC25A38 (c.409dupG) was identified in six unrelated patients and was a common variant in our population exhibiting ‘founder effect’.ConclusionThis is the largest series of sideroblastic anaemia cases with molecular characterisation from the Indian subcontinent.

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Phenotypic expression and founder effect of PANK2 c.1583C>T (p.T528M) mutation in Serbian pantothenate kinase-associated neurodegeneration patients

Archives of Biological Sciences ◽

10.2298/abs181227009s ◽

2019 ◽

Vol 71 (2) ◽

pp. 275-280

Author(s):

Marina Svetel ◽

Monika Hartig ◽

Dragana Cvetkovic ◽

Cyrielle Beaubois ◽

Jasmina Maksic ◽

...

Keyword(s):

Founder Effect ◽

Autosomal Recessive ◽

Common Ancestor ◽

Phenotypic Expression ◽

Autosomal Recessive Disorder ◽

Clinical Findings ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Pantothenate Kinase ◽

The Brain

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive disorder characterized by dystonia, parkinsonism, cognitive and visual impairment, and iron accumulation in the brain. Many cases of PKAN result from mutations in the PANK2 gene that encodes pantothenate kinase 2, a key regulatory enzyme in the biosynthesis of coenzyme A. We previously detected six Serbian patients with clinically suggestive PKAN, all of whom had PANK2 c.1583C>T (p.T528M) mutation either in the homozygous or in the heterozygous state. In this study we explored the phenotypic expression and a possible founder effect of this substitution. We performed the analysis of linkage disequilibrium (LD) and organization in haplotypes of 23 single nucleotide polymorphisms (SNPs) adjacent to the PANK2 gene in all of the six patients and their parents, as well as in control healthy child-parents trios. The age of PANK2 c.1583C>T mutation was determined using the r2 degeneration method. Clinical findings in our patients were markedly similar. Different LD structures between patients and controls is revealed, and PANK2 c.1583T allele was significantly associated with a particular haplotype. The age of PANK2 c.1583C>T mutation was estimated to be about 15 generations. Our results suggest that PANK2 c.1583C>T in Serbian PKAN patients represents a founder mutation descended from one common ancestor.

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Nuclear receptors in disease: the oestrogen receptors

Essays in Biochemistry ◽

10.1042/bse0400157 ◽

2004 ◽

Vol 40 ◽

pp. 157-167 ◽

Cited By ~ 18

Author(s):

Maria Nilsson ◽

Karin Dahlman-Wright ◽

Jan-Åke Gustafsson

Keyword(s):

Nuclear Receptors ◽

Target Genes ◽

Receptor Subtype ◽

Target Tissue ◽

Oestrogen Receptors ◽

Nucleotide Polymorphisms ◽

Cell Type ◽

Single Nucleotide ◽

Beneficial Effects ◽

The Family

For several decades, it has been known that oestrogens are essential for human health. The discovery that there are two oestrogen receptors (ERs), ERalpha and ERbeta, has facilitated our understanding of how the hormone exerts its physiological effects. The ERs belong to the family of ligand-activated nuclear receptors, which act by modulating the expression of target genes. Studies of ER-knockout (ERKO) mice have been instrumental in defining the relevance of a given receptor subtype in a certain tissue. Phenotypes displayed by ERKO mice suggest diseases in which dysfunctional ERs might be involved in aetiology and pathology. Association between single-nucleotide polymorphisms (SNPs) in ER genes and disease have been demonstrated in several cases. Selective ER modulators (SERMs), which are selective with regard to their effects in a certain cell type, already exist. Since oestrogen has effects in many tissues, the goal with a SERM is to provide beneficial effects in one target tissue while avoiding side effects in others. Refined SERMs will, in the future, provide improved therapeutic strategies for existing and novel indications.

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