Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.080
Filtrar
1.
Commun Biol ; 7(1): 831, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38977784

RESUMO

Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.


Assuntos
Deficiências do Desenvolvimento , Deficiência Intelectual , Microcefalia , Humanos , Microcefalia/genética , Microcefalia/patologia , Deficiência Intelectual/genética , Animais , Masculino , Feminino , Camundongos , Deficiências do Desenvolvimento/genética , Células HEK293 , Peixe-Zebra/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Pré-Escolar , Chlorocebus aethiops , Células COS , Criança , Neurônios/metabolismo , Neurônios/patologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo
2.
Int J Mol Sci ; 25(9)2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38731817

RESUMO

MCPH1 has been identified as the causal gene for primary microcephaly type 1, a neurodevelopmental disorder characterized by reduced brain size and delayed growth. As a multifunction protein, MCPH1 has been reported to repress the expression of TERT and interact with transcriptional regulator E2F1. However, it remains unclear whether MCPH1 regulates brain development through its transcriptional regulation function. This study showed that the knockout of Mcph1 in mice leads to delayed growth as early as the embryo stage E11.5. Transcriptome analysis (RNA-seq) revealed that the deletion of Mcph1 resulted in changes in the expression levels of a limited number of genes. Although the expression of some of E2F1 targets, such as Satb2 and Cdkn1c, was affected, the differentially expressed genes (DEGs) were not significantly enriched as E2F1 target genes. Further investigations showed that primary and immortalized Mcph1 knockout mouse embryonic fibroblasts (MEFs) exhibited cell cycle arrest and cellular senescence phenotype. Interestingly, the upregulation of p19ARF was detected in Mcph1 knockout MEFs, and silencing p19Arf restored the cell cycle and growth arrest to wild-type levels. Our findings suggested it is unlikely that MCPH1 regulates neurodevelopment through E2F1-mediated transcriptional regulation, and p19ARF-dependent cell cycle arrest and cellular senescence may contribute to the developmental abnormalities observed in primary microcephaly.


Assuntos
Pontos de Checagem do Ciclo Celular , Senescência Celular , Inibidor p16 de Quinase Dependente de Ciclina , Microcefalia , Animais , Camundongos , Pontos de Checagem do Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Senescência Celular/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/deficiência , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Fibroblastos/metabolismo , Camundongos Knockout , Microcefalia/genética , Microcefalia/metabolismo , Microcefalia/patologia
3.
Sci Rep ; 14(1): 9497, 2024 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664418

RESUMO

Raine syndrome (RNS) is a rare autosomal recessive osteosclerotic dysplasia. RNS is caused by loss-of-function disease-causative variants of the FAM20C gene that encodes a kinase that phosphorylates most of the secreted proteins found in the body fluids and extracellular matrix. The most common RNS clinical features are generalized osteosclerosis, facial dysmorphism, intracerebral calcifications and respiratory defects. In non-lethal RNS forms, oral traits include a well-studied hypoplastic amelogenesis imperfecta (AI) and a much less characterized gingival phenotype. We used immunomorphological, biochemical, and siRNA approaches to analyze gingival tissues and primary cultures of gingival fibroblasts of two unrelated, previously reported RNS patients. We showed that fibrosis, pathological gingival calcifications and increased expression of various profibrotic and pro-osteogenic proteins such as POSTN, SPARC and VIM were common findings. Proteomic analysis of differentially expressed proteins demonstrated that proteins involved in extracellular matrix (ECM) regulation and related to the TGFß/SMAD signaling pathway were increased. Functional analyses confirmed the upregulation of TGFß/SMAD signaling and subsequently uncovered the involvement of two closely related transcription cofactors important in fibrogenesis, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Knocking down of FAM20C confirmed the TGFß-YAP/TAZ interplay indicating that a profibrotic loop enabled gingival fibrosis in RNS patients. In summary, our in vivo and in vitro data provide a detailed description of the RNS gingival phenotype. They show that gingival fibrosis and calcifications are associated with, and most likely caused by excessed ECM production and disorganization. They furthermore uncover the contribution of increased TGFß-YAP/TAZ signaling in the pathogenesis of the gingival fibrosis.


Assuntos
Anormalidades Múltiplas , Proteínas Adaptadoras de Transdução de Sinal , Fissura Palatina , Hipoplasia do Esmalte Dentário , Exoftalmia , Fibroblastos , Fibrose , Gengiva , Osteosclerose , Proteômica , Transdução de Sinais , Fatores de Transcrição , Fator de Crescimento Transformador beta , Proteínas de Sinalização YAP , Humanos , Fator de Crescimento Transformador beta/metabolismo , Gengiva/metabolismo , Gengiva/patologia , Proteômica/métodos , Fibrose/metabolismo , Proteínas de Sinalização YAP/metabolismo , Proteínas de Sinalização YAP/genética , Osteosclerose/metabolismo , Osteosclerose/genética , Osteosclerose/patologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Hipoplasia do Esmalte Dentário/metabolismo , Hipoplasia do Esmalte Dentário/genética , Hipoplasia do Esmalte Dentário/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Microcefalia/metabolismo , Microcefalia/genética , Microcefalia/patologia , Feminino , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismo , Masculino , Transativadores/metabolismo , Transativadores/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Caseína Quinase I/metabolismo , Caseína Quinase I/genética , Proteínas da Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/genética , Amelogênese Imperfeita/metabolismo , Amelogênese Imperfeita/genética , Amelogênese Imperfeita/patologia , Células Cultivadas
4.
Genet Med ; 26(7): 101143, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38641995

RESUMO

PURPOSE: Neurodevelopmental disorders exhibit clinical and genetic heterogeneity, ergo manifest dysfunction in components of diverse cellular pathways; the precise pathomechanism for the majority remains elusive. METHODS: We studied 5 affected individuals from 3 unrelated families manifesting global developmental delay, postnatal microcephaly, and hypotonia. We used exome sequencing and prioritized variants that were subsequently characterized using immunofluorescence, immunoblotting, pulldown assays, and RNA sequencing. RESULTS: We identified biallelic variants in ZFTRAF1, encoding a protein of yet unknown function. Four affected individuals from 2 unrelated families segregated 2 homozygous frameshift variants in ZFTRAF1, whereas, in the third family, an intronic splice site variant was detected. We investigated ZFTRAF1 at the cellular level and signified it as a nucleocytoplasmic protein in different human cell lines. ZFTRAF1 was completely absent in the fibroblasts of 2 affected individuals. We also identified 110 interacting proteins enriched in mRNA processing and autophagy-related pathways. Based on profiling of autophagy markers, patient-derived fibroblasts show irregularities in the protein degradation process. CONCLUSION: Thus, our findings suggest that biallelic variants of ZFTRAF1 cause a severe neurodevelopmental disorder.


Assuntos
Mutação com Perda de Função , Microcefalia , Hipotonia Muscular , Transtornos do Neurodesenvolvimento , Linhagem , Humanos , Microcefalia/genética , Microcefalia/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Masculino , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Feminino , Pré-Escolar , Mutação com Perda de Função/genética , Alelos , Criança , Lactente , Sequenciamento do Exoma , Fibroblastos/metabolismo , Fibroblastos/patologia , Autofagia/genética
5.
Am J Med Genet A ; 194(8): e63581, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38600862

RESUMO

Alu elements are short, interspersed elements located throughout the genome, playing a role in human diversity, and occasionally causing genetic diseases. Here, we report a novel Alu insertion causing Mowat-Wilson syndrome, a rare neurodevelopmental disorder, in an 8-year-old boy displaying the typical clinical features for Mowat-Wilson syndrome. The variant was not initially detected in genome sequencing data, but through deep phenotyping, which pointed to only one plausible candidate gene, manual inspection of genome sequencing alignment data enabled us to identify a de novo heterozygous Alu insertion in exon 8 of the ZEB2 gene. Nanopore long-read sequencing confirmed the Alu insertion, leading to the formation of a premature stop codon and likely haploinsufficiency of ZEB2. This underscores the importance of deep phenotyping and mobile element insertion analysis in uncovering genetic causes of monogenic disorders as these elements might be overlooked in standard next-generation sequencing protocols.


Assuntos
Elementos Alu , Fácies , Doença de Hirschsprung , Deficiência Intelectual , Microcefalia , Homeobox 2 de Ligação a E-box com Dedos de Zinco , Humanos , Elementos Alu/genética , Microcefalia/genética , Microcefalia/patologia , Masculino , Criança , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Doença de Hirschsprung/genética , Doença de Hirschsprung/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Fenótipo , Mutagênese Insercional/genética , Sequenciamento de Nucleotídeos em Larga Escala , Éxons/genética
6.
Mol Genet Genomic Med ; 12(4): e2426, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38562046

RESUMO

BACKGROUND: Mandibulofacial dysostosis with microcephaly (MFDM, OMIM# 610536) is a rare monogenic disease that is caused by a mutation in the elongation factor Tu GTP binding domain containing 2 gene (EFTUD2, OMIM* 603892). It is characterized by mandibulofacial dysplasia, microcephaly, malformed ears, cleft palate, growth and intellectual disability. MFDM can be easily misdiagnosed due to its phenotypic overlap with other craniofacial dysostosis syndromes. The clinical presentation of MFDM is highly variable among patients. METHODS: A patient with craniofacial anomalies was enrolled and evaluated by a multidisciplinary team. To make a definitive diagnosis, whole-exome sequencing was performed, followed by validation by Sanger sequencing. RESULTS: The patient presented with extensive facial bone dysostosis, upward slanting palpebral fissures, outer and middle ear malformation, a previously unreported orbit anomaly, and spina bifida occulta. A novel, pathogenic insertion mutation (c.215_216insT: p.Tyr73Valfs*4) in EFTUD2 was identified as the likely cause of the disease. CONCLUSIONS: We diagnosed this atypical case of MFDM by the detection of a novel pathogenetic mutation in EFTUD2. We also observed previously unreported features. These findings enrich both the genotypic and phenotypic spectrum of MFDM.


Assuntos
Deficiência Intelectual , Disostose Mandibulofacial , Microcefalia , Humanos , Microcefalia/patologia , Disostose Mandibulofacial/genética , Disostose Mandibulofacial/patologia , Fenótipo , Mutação , Deficiência Intelectual/genética , Fatores de Alongamento de Peptídeos/genética , Fatores de Alongamento de Peptídeos/metabolismo , Ribonucleoproteína Nuclear Pequena U5/genética , Ribonucleoproteína Nuclear Pequena U5/metabolismo
7.
Genes (Basel) ; 15(4)2024 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-38674371

RESUMO

The adaptor protein 4 (AP-4) constitutes a conserved hetero-tetrameric complex within the family of adaptor protein (AP) complex, crucial for the signal-mediated trafficking of integral membrane proteins. Mutations affecting all subunits of the AP-4 complex have been linked to autosomal-recessive cerebral palsy and a complex hereditary spastic paraparesis (HSP) phenotype. Our report details the case of a 14-year-old boy born to consanguineous parents, presenting psychomotor delay, severe intellectual disability, microcephaly, and trigonocephaly. Despite a history of febrile seizures, subsequent years were devoid of seizures, with normal EEG. Exome sequencing revealed pathogenic variants in both the AP4B1 and ERF genes. Significantly, the patient exhibited features associated with AP4B1 mutations, including distinctive traits such as cranial malformations. The ERF gene variant, linked to craniosynostosis, likely contributes to the observed trigonocephaly. This case represents the initial documentation of a concurrent mutation in the AP4B1 and ERF genes, underscoring the critical role of exome analysis in unraveling complex phenotypes. Understanding these complex genotypes offers valuable insights into broader syndromic conditions, facilitating comprehensive patient management.


Assuntos
Complexo 4 de Proteínas Adaptadoras , Mutação , Fatores de Terminação de Peptídeos , Fenótipo , Proteínas Repressoras , Humanos , Masculino , Adolescente , Fatores de Terminação de Peptídeos/genética , Complexo 4 de Proteínas Adaptadoras/genética , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Sequenciamento do Exoma , Microcefalia/genética , Microcefalia/patologia , Craniossinostoses/genética , Craniossinostoses/patologia
8.
Eur J Med Genet ; 69: 104939, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38614309

RESUMO

ADH5/ALDH2 deficiency is a rare inherited syndrome characterized by short stature, microcephaly, delayed mental development, and hematopoietic dysfunction and has recently been proposed as a disease paradigm. Acute and severe presentations include aplastic anemia, myelodysplastic syndrome, or leukemia, requiring bone marrow transplantation during childhood. Conversely, non-hematological manifestations may exhibit a prolonged and nonspecific clinical trajectory, with growth failure and developmental delay, most of which are often overlooked, particularly in patients with milder symptoms. Here, we describe the clinical course of a girl with a wide spectrum of clinical presentations, including nonspecific hematopoietic disorders, growth retardation, mild developmental delay, amblyopia, hemophagocytic lymphohistiocytosis, and verruca vulgaris, culminating in a genetic diagnosis of AMeD syndrome at 12 years of age. We also summarized the clinical manifestations of previously reported cases of AMeD syndrome. Cumulatively, 13 females and 5 males have been documented, with a cardinal triad of symptoms, aplastic anemia, short stature, and intellectual disability. Additional characteristic observations included pigmentary deposition in approximately half of the cases and skeletal difficulties in one-quarter. We propose that early diagnosis of patients who exhibit relatively mild phenotypes of skin or skeletal lesions is important for managing and improving the quality of life of patients with AMeD syndrome.


Assuntos
Fenótipo , Humanos , Feminino , Criança , Aldeído-Desidrogenase Mitocondrial/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Masculino , Microcefalia/genética , Microcefalia/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Anemia Aplástica/genética , Anemia Aplástica/patologia
9.
Eur J Med Genet ; 69: 104942, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38677542

RESUMO

Telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly (TEBC) syndrome is a rare autosomal dominant condition, recently linked to the protein kinase D1 (PRKD1) gene. The phenotype of TEBC remains incomplete at this point. Our aim is to improve the characterization of the clinical and molecular aspects of the TEBC syndrome. We report on the 8th patient carrying a heterozygous de novo variation of PRKD1 c.2134G > A, p. (Val712Met) identified by trio exome sequencing. The proband presents with partial atrioventricular septal defect, brachydactyly, ectodermal dysplasia, telangiectasia that developed in childhood, intellectual disability with microcephaly, multicystic renal dysplasia and moderate hormonal resistance. In view of this 8th description and review of the literature, it appears that neurodevelopmental disorders and microcephaly are frequently associated with PRKD1 missense variants, adding to the four main clinical signs described initially in the TEBC syndrome. Further descriptions are required to confirm the observed endocrine and kidney abnormalities. This should contribute to a more comprehensive understanding of the phenotypic spectrum and may help establish genotype-phenotype correlations. In the context of genotype-first strategy, accurate patient descriptions are fundamental. Characterization of specific syndromic associations is essential for variant interpretation support and patient follow-up, even in very rare diseases, such as the TEBC syndrome.


Assuntos
Displasia Ectodérmica , Cardiopatias Congênitas , Humanos , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Fenótipo , Braquidactilia/genética , Braquidactilia/patologia , Masculino , Telangiectasia/genética , Telangiectasia/patologia , Feminino , Mutação de Sentido Incorreto , Síndrome , Microcefalia/genética , Microcefalia/patologia , Criança , Proteína Quinase C
10.
EMBO Rep ; 25(5): 2418-2440, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38605277

RESUMO

Microcephaly is a common feature in inherited bone marrow failure syndromes, prompting investigations into shared pathways between neurogenesis and hematopoiesis. To understand this association, we studied the role of the microcephaly gene Mcph1 in hematological development. Our research revealed that Mcph1-knockout mice exhibited congenital macrocytic anemia due to impaired terminal erythroid differentiation during fetal development. Anemia's cause is a failure to complete cell division, evident from tetraploid erythroid progenitors with DNA content exceeding 4n. Gene expression profiling demonstrated activation of the p53 pathway in Mcph1-deficient erythroid precursors, leading to overexpression of Cdkn1a/p21, a major mediator of p53-dependent cell cycle arrest. Surprisingly, fetal brain analysis revealed hypertrophied binucleated neuroprogenitors overexpressing p21 in Mcph1-knockout mice, indicating a shared pathophysiological mechanism underlying both erythroid and neurological defects. However, inactivating p53 in Mcph1-/- mice failed to reverse anemia and microcephaly, suggesting that p53 activation in Mcph1-deficient cells resulted from their proliferation defect rather than causing it. These findings shed new light on Mcph1's function in fetal hematopoietic development, emphasizing the impact of disrupted cell division on neurogenesis and erythropoiesis - a common limiting pathway.


Assuntos
Proteínas de Ciclo Celular , Inibidor de Quinase Dependente de Ciclina p21 , Eritropoese , Camundongos Knockout , Microcefalia , Proteína Supressora de Tumor p53 , Animais , Eritropoese/genética , Microcefalia/genética , Microcefalia/patologia , Camundongos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Mutação , Anemia Macrocítica/genética , Anemia Macrocítica/patologia , Anemia Macrocítica/metabolismo , Diferenciação Celular/genética , Células Precursoras Eritroides/metabolismo
11.
Am J Med Genet A ; 194(7): e63598, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38501757

RESUMO

Primary microcephaly is characterized by a head circumference prenatally or at birth that falls below three standard deviations from age-, ethnic-, and sex-specific norms. Genetic defects are one of the underlying causes of primary microcephaly. Since 2014, five variants of the SASS6 gene have been identified as the cause of MCPH 14 in three reported families. In this study, we present the genetic findings of members of a nonconsanguineous Chinese couple with a history of microcephaly and fetal growth restriction (FGR) during their first pregnancy. Utilizing trio whole-exome sequencing, we identified compound heterozygous variants involving a frameshift NM_194292.3:c.450_453del p.(Lys150AsnfsTer7) variant and a splice region NM_194292.3:c.1674+3A>G variant within the SASS6 gene in the affected fetus. Moreover, reverse transcriptase-polymerase chain reaction from RNA of the mother's peripheral blood leukocytes revealed that the c.1674+3A>G variant led to the skipping of exon 14 and an inframe deletion. To the best of our knowledge, the association between FGR and SASS6-related microcephaly has not been reported, and our findings confirm the pivotal role of SASS6 in microcephaly pathogenesis and reveal an expanded view of the phenotype and mutation spectrum associated with this gene.


Assuntos
Alelos , Sequenciamento do Exoma , Retardo do Crescimento Fetal , Microcefalia , Humanos , Microcefalia/genética , Microcefalia/patologia , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Feminino , Masculino , Gravidez , Linhagem , Mutação/genética , Adulto , Predisposição Genética para Doença , Fenótipo
12.
Am J Med Genet A ; 194(7): e63599, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38517182

RESUMO

Pathogenic variants in TRIO, encoding the guanine nucleotide exchange factor, are associated with two distinct neurodevelopmental delay phenotypes: gain-of-function missense mutations within the spectrin repeats are causative for a severe developmental delay with macrocephaly (MIM: 618825), whereas loss-of-function missense variants in the GEF1 domain and truncating variants throughout the gene lead to a milder developmental delay and microcephaly (MIM: 617061). In three affected family members with mild intellectual disability/NDD and microcephaly, we detected a novel heterozygous TRIO variant at the last coding base of exon 31 (NM_007118.4:c.4716G>A). RNA analysis from patient-derived lymphoblastoid cells confirmed aberrant splicing resulting in the skipping of exon 31 (r.4615_4716del), leading to an in-frame deletion in the first Pleckstrin homology subdomain of the GEF1 domain: p.(Thr1539_Lys1572del). To test for a distinct gestalt, facial characteristics of the family members and 41 previously published TRIO cases were systematically evaluated via GestaltMatcher. Computational analysis of the facial gestalt suggests a distinguishable facial TRIO-phenotype not outlined in the existing literature.


Assuntos
Fatores de Troca do Nucleotídeo Guanina , Linhagem , Fenótipo , Sítios de Splice de RNA , Humanos , Fatores de Troca do Nucleotídeo Guanina/genética , Masculino , Feminino , Sítios de Splice de RNA/genética , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Microcefalia/genética , Microcefalia/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Éxons/genética , Splicing de RNA/genética , Fácies , Proteínas Serina-Treonina Quinases
13.
Am J Med Genet A ; 194(8): e63593, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38549403

RESUMO

Biallelic pathogenic variants in ZNF335 are one of the genetic causes of microcephaly, reported only in the past decade. It regulates neural progenitor proliferation and neurogenesis by interacting with a H3K4 methyltransferase complex. Biallelic pathogenic ZNF335 variants predispose to neuronal cell death and aberrant differentiation, thus causing secondary microcephaly. These neurodevelopmental anomalies lead to imaging findings in the cortex, posterior fossa, and basal ganglia. We report an individual of Nepalese ancestry with a novel homozygous ZNF335 variant (c.3591 + 2dup) (p.?) (NM_022095.3) which on further RNA analysis confirmed a splice site variant in intron 23. The patient presented with primary microcephaly with atrophic cerebral hemispheres, oversimplification of gyri, basal ganglia, and corpus callosal atrophy. Literature review on the topic revealed a spectrum of brain abnormalities, which can present either with a primary or secondary microcephaly depending upon the underlying genetic variant.


Assuntos
Alelos , Proteínas de Ligação a DNA , Microcefalia , Fatores de Transcrição , Humanos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/anormalidades , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Homozigoto , Imageamento por Ressonância Magnética , Microcefalia/genética , Microcefalia/patologia , Mutação/genética , Fatores de Transcrição/genética
14.
Exp Neurol ; 374: 114699, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38301864

RESUMO

The congenital Zika syndrome (CZS) has been characterized as a set of several brain changes, such as reduced brain volume and subcortical calcifications, in addition to cognitive deficits. Microcephaly is one of the possible complications found in newborns exposed to Zika virus (ZIKV) during pregnancy, although it is an impacting clinical sign. This study aimed to investigate the consequences of a model of congenital ZIKV infection by evaluating the histopathology, blood-brain barrier, and neuroinflammation in pup rats 24 h after birth, and neurodevelopment of the offspring. Pregnant rats were inoculated subcutaneously with ZIKV-BR at the dose 1 × 107 plaque-forming unit (PFU mL-1) of ZIKV isolated in Brazil (ZIKV-BR) on gestational day 18 (G18). A set of pups, 24 h after birth, was euthanized. The brain was collected and later evaluated for the histopathology of brain structures through histological analysis. Additionally, analyses of the blood-brain barrier were conducted using western blotting, and neuroinflammation was assessed using ELISA. Another set of animals was evaluated on postnatal days 3, 6, 9, and 12 for neurodevelopment by observing the developmental milestones. Our results revealed hippocampal atrophy in ZIKV animals, in addition to changes in the blood-brain barrier structure and pro-inflammatory cytokines expression increase. Regarding neurodevelopment, a delay in important reflexes during the neonatal period in ZIKV animals was observed. These findings advance the understanding of the pathophysiology of CZS and contribute to enhancing the rat model of CZS.


Assuntos
Microcefalia , Complicações Infecciosas na Gravidez , Infecção por Zika virus , Zika virus , Gravidez , Humanos , Feminino , Ratos , Animais , Infecção por Zika virus/complicações , Infecção por Zika virus/diagnóstico , Zika virus/fisiologia , Complicações Infecciosas na Gravidez/patologia , Barreira Hematoencefálica/patologia , Doenças Neuroinflamatórias , Microcefalia/etiologia , Microcefalia/patologia , Atrofia/patologia , Hipocampo/patologia
15.
Genet Med ; 26(6): 101104, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38411040

RESUMO

PURPOSE: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system. METHODS: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences. RESULTS: Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models. CONCLUSION: A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients.


Assuntos
Proteínas Ferro-Enxofre , Peixe-Zebra , Animais , Humanos , Proteínas Ferro-Enxofre/genética , Proteínas Ferro-Enxofre/metabolismo , Masculino , Feminino , Fenótipo , Fibroblastos/metabolismo , Fibroblastos/patologia , Citosol/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Microcefalia/genética , Microcefalia/patologia , Lactente , Metalochaperonas
16.
Eur J Hum Genet ; 32(6): 619-629, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38351292

RESUMO

Mowat-Wilson syndrome (MOWS) is a rare congenital disease caused by haploinsufficiency of ZEB2, encoding a transcription factor required for neurodevelopment. MOWS is characterized by intellectual disability, epilepsy, typical facial phenotype and other anomalies, such as short stature, Hirschsprung disease, brain and heart defects. Despite some recognizable features, MOWS rarity and phenotypic variability may complicate its diagnosis, particularly in the neonatal period. In order to define a novel diagnostic biomarker for MOWS, we determined the genome-wide DNA methylation profile of DNA samples from 29 individuals with confirmed clinical and molecular diagnosis. Through multidimensional scaling and hierarchical clustering analysis, we identified and validated a DNA methylation signature involving 296 differentially methylated probes as part of the broader MOWS DNA methylation profile. The prevalence of hypomethylated CpG sites agrees with the main role of ZEB2 as a transcriptional repressor, while differential methylation within the ZEB2 locus supports the previously proposed autoregulation ability. Correlation studies compared the MOWS cohort with 56 previously described DNA methylation profiles of other neurodevelopmental disorders, further validating the specificity of this biomarker. In conclusion, MOWS DNA methylation signature is highly sensitive and reproducible, providing a useful tool to facilitate diagnosis.


Assuntos
Metilação de DNA , Fácies , Doença de Hirschsprung , Proteínas de Homeodomínio , Deficiência Intelectual , Microcefalia , Proteínas Repressoras , Homeobox 2 de Ligação a E-box com Dedos de Zinco , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Microcefalia/genética , Microcefalia/diagnóstico , Microcefalia/patologia , Doença de Hirschsprung/genética , Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/patologia , Proteínas de Homeodomínio/genética , Proteínas Repressoras/genética , Feminino , Masculino , Criança , Pré-Escolar , Adolescente , Ilhas de CpG
17.
Mol Genet Genomic Med ; 12(1): e2310, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37902276

RESUMO

BACKGROUND: Bi-allelic variants in AFG2B (previously known as SPATA5L1) have recently been associated with a neurodevelopmental disorder with hearing loss and spasticity, as well as isolated hearing loss. We report on a 6 1/2-year-old girl with a history of global developmental delay, subsequent intellectual disability without relevant language acquisition, sensorineural hearing loss, muscular hypotonia and microcephaly. METHODS: We performed trio exome sequencing on the patient and her parents. RESULTS: Trio exome sequencing revealed likely pathogenic compound heterozygous missense variants in AFG2B [c.527G>T, p.(Gly176Val) and c.1313T>C, p.(Leu438Pro)] in the patient. CONCLUSION: Of note, the change c.1313T>C, p.(Leu438Pro) has been observed in a previously published patient as part of a complex disease allele along with a second homozygous missense change, so the exact contribution of the two alterations to this patient's disease had initially remained unclear. Our results support the pathogenic relevance of the c.1313T>C, p.(Leu438Pro) allele while providing detailed insights into the disease manifestation of a further patient.


Assuntos
Surdez , Microcefalia , Malformações do Sistema Nervoso , Transtornos do Neurodesenvolvimento , Humanos , Feminino , Pessoa de Meia-Idade , Microcefalia/genética , Microcefalia/patologia , Virulência , Transtornos do Neurodesenvolvimento/genética
18.
Am J Med Genet A ; 194(3): e63468, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37937525

RESUMO

Primary microcephaly (MCPH) is an autosomal recessive disorder characterized by head circumference of at least two standard deviations below the mean. Biallelic variants in the kinetochore gene KNL1 is a known cause of MCPH4. KNL1 is the central component of the KNL1-MIS12-NSL1 (KMN) network, which acts as the signaling hub of the kinetochore and is required for correct chromosomal segregation during mitosis. We identified biallelic KNL1 variants in two siblings from a non-consanguineous family with microcephaly and intellectual disability. The two siblings carry a frameshift variant predicted to prematurely truncate the transcript and undergo nonsense mediated decay, and an intronic single nucleotide variant (SNV) predicted to disrupt splicing. An in vitro splicing assay and qPCR from blood-derived RNA confirmed that the intronic variant skips exon 23, significantly reducing levels of the canonical transcript. Protein modeling confirmed that absence of exon 23, an inframe exon, would disrupt a key interaction within the KMN network and likely destabilize the kinetochore signaling hub, disrupting mitosis. Therefore, this splicing variant is pathogenic and, in trans with a frameshift variant, causes the MCPH phenotype associated with KLN1. This finding furthers the association of splicing variants as a common pathogenic variant class for KNL1.


Assuntos
Cinetocoros , Microcefalia , Humanos , Proteínas de Ciclo Celular/genética , Cinetocoros/metabolismo , Cinetocoros/patologia , Microcefalia/genética , Microcefalia/patologia , Proteínas Associadas aos Microtúbulos/genética , Mutação
19.
Mol Genet Genomic Med ; 12(1): e2295, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37916443

RESUMO

BACKGROUND: Microcephaly with early-onset seizures (MCSZ) is a neurodevelopmental disorder caused by pathogenic variants in the DNA strand break repair protein, polynucleotide kinase 3'-phosphatase (PNKP). METHODS: We have used whole genome sequencing and Sanger sequencing to identify disease-causing variants, followed by a minigene assay, Western blotting, alkaline comet assay, γH2AX, and ADP-ribose immunofluorescence. RESULTS: Here, we describe a patient with compound heterozygous variants in PNKP, including a missense variant in the DNA phosphatase domain (T323M) and a novel splice acceptor site variant within the DNA kinase domain that we show leads to exon skipping. We show that primary fibroblasts derived from the patient exhibit greatly reduced levels of PNKP protein and reduced rates of DNA single-strand break repair, confirming that the mutated PNKP alleles are dysfunctional. CONCLUSION: The data presented show that the detected compound heterozygous variants result in reduced levels of PNKP protein, which affect the repair of both oxidative and TOP1-induced single-strand breaks, and most likely causes MCSZ in this patient.


Assuntos
Enzimas Reparadoras do DNA , Microcefalia , Humanos , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Microcefalia/genética , Microcefalia/patologia , Mutação , Convulsões/genética , DNA , Monoéster Fosfórico Hidrolases/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
20.
Eur J Med Genet ; 66(11): 104852, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37758168

RESUMO

Defects in L-serine biosynthesis are a group of autosomal recessive diseases resulting in a wide phenotypic spectrum ranging from viable to lethal presentations and caused by variants in the three genes encoding the L-serine biosynthesis enzymes, PHGDH, PSAT1, and PSPH. Neu-Laxova syndrome (NLS) is the fetal form of this group, characterized by multiple congenital anomalies including severe intrauterine growth retardation, cutaneous lesions extending from ichthyosis to severe restrictive dermopathy with ectropion and eclabion, edema, microcephaly, central nervous system abnormalities, and flexion contractures. Here we report on two unrelated fetuses with an attenuated phenotype of NLS, that initially evoked Taybi-Linder syndrome. They carry biallelic pathogenic variants in the PHGDH gene. These observations expand the phenotypic continuum of L-serine biosynthesis defects, and illustrate the phenotypic overlap between NLS and microcephalic primordial dwarfism.


Assuntos
Nanismo , Microcefalia , Feminino , Humanos , Microcefalia/genética , Microcefalia/patologia , Feto/patologia , Nanismo/genética , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Serina
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...