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1.
Hum Genet ; 143(7): 921-938, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39060644

RESUMO

In recent years, there has been increased focus on exploring the role the non-protein-coding genome plays in Mendelian disorders. One class of particular interest is long non-coding RNAs (lncRNAs), which has recently been implicated in the regulation of diverse molecular processes. However, because lncRNAs do not encode protein, there is uncertainty regarding what constitutes a pathogenic lncRNA variant, and thus annotating such elements is challenging. The Developmental Genome Anatomy Project (DGAP) and similar projects recruit individuals with apparently balanced chromosomal abnormalities (BCAs) that disrupt or dysregulate genes in order to annotate the human genome. We hypothesized that rearrangements disrupting lncRNAs could be the underlying genetic etiology for the phenotypes of a subset of these individuals. Thus, we assessed 279 cases with BCAs and selected 191 cases with simple BCAs (breakpoints at only two genomic locations) for further analysis of lncRNA disruptions. From these, we identified 66 cases in which the chromosomal rearrangements directly disrupt lncRNAs. In 30 cases, no genes of any other class aside from lncRNAs are directly disrupted, consistent with the hypothesis that lncRNA disruptions could underly the phenotypes of these individuals. Strikingly, the lncRNAs MEF2C-AS1 and ENSG00000257522 are each disrupted in two unrelated cases. Furthermore, we experimentally tested the lncRNAs TBX2-AS1 and MEF2C-AS1 and found that knockdown of these lncRNAs resulted in decreased expression of the neighboring transcription factors TBX2 and MEF2C, respectively. To showcase the power of this genomic approach for annotating lncRNAs, here we focus on clinical reports and genetic analysis of seven individuals with likely developmental etiologies due to lncRNA disruptions.


Assuntos
Fatores de Transcrição MEF2 , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Fatores de Transcrição MEF2/genética , Feminino , Aberrações Cromossômicas , Masculino , Genoma Humano , Fenótipo , Mutação em Linhagem Germinativa
2.
Brain ; 141(4): 961-970, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29522154

RESUMO

RSRC1, whose polymorphism is associated with altered brain function in schizophrenia, is a member of the serine and arginine rich-related protein family. Through homozygosity mapping and whole exome sequencing we show that RSRC1 mutation causes an autosomal recessive syndrome of intellectual disability, aberrant behaviour, hypotonia and mild facial dysmorphism with normal brain MRI. Further, we show that RSRC1 is ubiquitously expressed, and that the RSRC1 mutation triggers nonsense-mediated mRNA decay of the RSRC1 transcript in patients' fibroblasts. Short hairpin RNA (shRNA)-mediated lentiviral silencing and overexpression of RSRC1 in SH-SY5Y cells demonstrated that RSRC1 has a role in alternative splicing and transcription regulation. Transcriptome profiling of RSRC1-silenced cells unravelled specific differentially expressed genes previously associated with intellectual disability, hypotonia and schizophrenia, relevant to the disease phenotype. Protein-protein interaction network modelling suggested possible intermediate interactions by which RSRC1 affects gene-specific differential expression. Patient-derived induced pluripotent stem cells, differentiated into neural progenitor cells, showed expression dynamics similar to the RSRC1-silenced SH-SY5Y model. Notably, patient neural progenitor cells had 9.6-fold downregulated expression of IGFBP3, whose brain expression is affected by MECP2, aberrant in Rett syndrome. Interestingly, Igfbp3-null mice have behavioural impairment, abnormal synaptic function and monoaminergic neurotransmission, likely correlating with the disease phenotype.


Assuntos
Processamento Alternativo/genética , Deficiências do Desenvolvimento/genética , Regulação para Baixo/genética , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Deficiência Intelectual/genética , Proteínas Nucleares/genética , Animais , Diferenciação Celular/genética , Linhagem Celular Transformada , Criança , Pré-Escolar , Consanguinidade , Deficiências do Desenvolvimento/complicações , Feminino , Seguimentos , Ontologia Genética , Humanos , Lactente , Deficiência Intelectual/complicações , Masculino , Camundongos , Camundongos Knockout , Células-Tronco Pluripotentes/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo
3.
Am J Hum Genet ; 90(5): 893-9, 2012 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-22521417

RESUMO

Meconium ileus, intestinal obstruction in the newborn, is caused in most cases by CFTR mutations modulated by yet-unidentified modifier genes. We now show that in two unrelated consanguineous Bedouin kindreds, an autosomal-recessive phenotype of meconium ileus that is not associated with cystic fibrosis (CF) is caused by different homozygous mutations in GUCY2C, leading to a dramatic reduction or fully abrogating the enzymatic activity of the encoded guanlyl cyclase 2C. GUCY2C is a transmembrane receptor whose extracellular domain is activated by either the endogenous ligands, guanylin and related peptide uroguanylin, or by an external ligand, Escherichia coli (E. coli) heat-stable enterotoxin STa. GUCY2C is expressed in the human intestine, and the encoded protein activates the CFTR protein through local generation of cGMP. Thus, GUCY2C is a likely candidate modifier of the meconium ileus phenotype in CF. Because GUCY2C heterozygous and homozygous mutant mice are resistant to E. coli STa enterotoxin-induced diarrhea, it is plausible that GUCY2C mutations in the desert-dwelling Bedouin kindred are of selective advantage.


Assuntos
Obstrução Intestinal/genética , Obstrução Intestinal/metabolismo , Mecônio/metabolismo , Mutação , Receptores Acoplados a Guanilato Ciclase/genética , Receptores de Peptídeos/genética , Sequência de Aminoácidos , Animais , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/toxicidade , GMP Cíclico/metabolismo , Fibrose Cística/genética , Fibrose Cística/fisiopatologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Diarreia/etiologia , Diarreia/metabolismo , Diarreia/fisiopatologia , Regulação para Baixo , Enterotoxinas/metabolismo , Enterotoxinas/toxicidade , Proteínas de Escherichia coli , Feminino , Hormônios Gastrointestinais/metabolismo , Genes Modificadores , Células HEK293 , Heterozigoto , Humanos , Mucosa Intestinal/metabolismo , Obstrução Intestinal/fisiopatologia , Masculino , Camundongos , Dados de Sequência Molecular , Peptídeos Natriuréticos/metabolismo , Linhagem , Fenótipo , Receptores de Enterotoxina , Receptores Acoplados a Guanilato Ciclase/metabolismo , Receptores de Peptídeos/metabolismo
4.
medRxiv ; 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38946951

RESUMO

In recent years, there has been increased focus on exploring the role the non-protein-coding genome plays in Mendelian disorders. One class of particular interest is long non-coding RNAs (lncRNAs), which has recently been implicated in the regulation of diverse molecular processes. However, because lncRNAs do not encode protein, there is uncertainty regarding what constitutes a pathogenic lncRNA variant, and thus annotating such elements is challenging. The Developmental Genome Anatomy Project (DGAP) and similar projects recruit individuals with apparently balanced chromosomal abnormalities (BCAs) that disrupt or dysregulate genes in order to annotate the human genome. We hypothesized that rearrangements disrupting lncRNAs could be the underlying genetic etiology for the phenotypes of a subset of these individuals. Thus, we assessed 279 cases with BCAs and selected 191 cases with simple BCAs (breakpoints at only two genomic locations) for further analysis of lncRNA disruptions. From these, we identified 66 cases in which the chromosomal rearrangements directly disrupt lncRNAs. Strikingly, the lncRNAs MEF2C-AS1 and ENSG00000257522 are each disrupted in two unrelated cases. Furthermore, in 30 cases, no genes of any other class aside from lncRNAs are directly disrupted, consistent with the hypothesis that lncRNA disruptions could underly the phenotypes of these individuals. To showcase the power of this genomic approach for annotating lncRNAs, here we focus on clinical reports and genetic analysis of two individuals with BCAs and additionally highlight six individuals with likely developmental etiologies due to lncRNA disruptions.

5.
Am J Hum Genet ; 87(5): 713-20, 2010 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-21035102

RESUMO

Excessive chloride secretion in sweat (hyperchlorhidrosis), leading to a positive sweat test, is most commonly indicative of cystic fibrosis yet is found also in conjunction with various metabolic, endocrine, and dermatological disorders. There is conflicting evidence regarding the existence of autosomal-recessive hyperchlorhidrosis. We now describe a consanguineous Israeli Bedouin kindred with autosomal-recessive hyperchlohidrosis whose sole symptoms are visible salt precipitates after sweating, a preponderance to hyponatremic dehydration, and poor feeding and slow weight gain at infancy. Through genome-wide linkage analysis, we demonstrate that the phenotype is due to a homozygous mutation in CA12, encoding carbonic anhydrase XII. The mutant (c.427G>A [p.Glu143Lys]) protein showed 71% activity of the wild-type enzyme for catalyzing the CO2 hydration to bicarbonate and H(+), and it bound the clinically used sulfonamide inhibitor acetazolamide with high affinity (K(I) of 10 nM). Unlike the wild-type enzyme, which is not inhibited by chloride, bromide, or iodide (K(I)s of 73-215 mM), the mutant is inhibited in the submicromolar range by these anions (K(I)s of 0.37-0.73 mM).


Assuntos
Anidrases Carbônicas/genética , Hiperidrose/genética , Cloreto de Sódio/metabolismo , Suor/metabolismo , Mapeamento Cromossômico , Cromossomos Humanos Par 15 , Feminino , Homozigoto , Humanos , Masculino , Mutação , Linhagem
6.
Harefuah ; 151(12): 662-4, 722, 2012 Dec.
Artigo em Hebraico | MEDLINE | ID: mdl-23330254

RESUMO

Cirrhotic portal hypertension is the major cause of ascites. Ascites is the most common expression of decompensated liver disease. However, other etiologies may occur and may pose a diagnostic and therapeutic challenge. A patient with chronic hepatitis C and an unusual cause of ascites is presented.


Assuntos
Ascite/etiologia , Hepatite C Crônica/complicações , Ascite/diagnóstico , Ascite/virologia , Humanos , Masculino , Pessoa de Meia-Idade
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