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1.
J Comput Assist Tomogr ; 44(5): 704-707, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32842072

RESUMO

PURPOSE: Incomplete partition III (IP-III), characterized by congenital mixed or sensorineural hearing loss, is a rare genetic disease transmitted through X-linked mode of inheritance. Inner ear findings of IP-III have been well described and allow an immediate diagnosis to be made. Recently, an association between IP-III and distinct hypothalamic malformations has been reported in some of the patients with IP-III. The purpose of this study was to investigate the morphologic abnormalities of the hypothalamus in IP-III. MATERIALS AND METHODS: Magnetic resonance imaging studies of 8 subjects, including 1 set of brothers, who were diagnosed with IP-III based on their clinical and inner ear imaging findings, were analyzed. RESULTS: Of the 8 subjects, 7 demonstrated some degree of morphologic abnormality of the hypothalamus. Of these, 2 showed asymmetrical thickening, 1 showed symmetrical thickening, and 4 showed mass-like enlargement of the hypothalamus. Six of 7 subjects with hypothalamic abnormalities showed asymmetry in caudal extension of the abnormalities, which was more discernible on coronal oblique T2-weighted images. Clinically, none of the subjects had endocrinologic or neurologic symptoms. CONCLUSIONS: This retrospective analysis presents further magnetic resonance imaging evidence on the association between the rare IP-III malformations and the presence of hypothalamic morphologic abnormalities.


Assuntos
Orelha Interna , Doenças Genéticas Ligadas ao Cromossomo X , Perda Auditiva Neurossensorial , Hipotálamo , Adolescente , Adulto , Idoso , Pré-Escolar , Orelha Interna/anormalidades , Orelha Interna/diagnóstico por imagem , Orelha Interna/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/patologia , Humanos , Hipotálamo/anormalidades , Hipotálamo/diagnóstico por imagem , Hipotálamo/patologia , Imagem por Ressonância Magnética , Masculino , Estudos Retrospectivos , Adulto Jovem
2.
Autoimmun Rev ; 19(6): 102526, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32234571

RESUMO

BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder characterized by early onset fatal multi-system autoimmunity due to loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor which is crucial for the development, maturation, and maintenance of CD4+ regulatory T (T-reg) cells. Various autoimmune phenomena such as enteropathy, endocrinopathies, cytopenias, renal disease, and skin manifestations are characteristic findings in patients affected by IPEX syndrome. OBJECTIVES: In this systematic review, we focus on both clinical and demographic characteristics of IPEX patients, highlighting possible genotype-phenotype correlations and address prognostic factors for disease outcome. METHODS: We performed a literature search to systematically investigate the case reports of IPEX which were published before August 7th, 2017. RESULTS: A total of 75 articles (195 patients) were identified. All IPEX patients included had FOXP3 mutations which were most frequently located in the forkhead domain (n = 68, 34.9%) followed by the leucine-zipper domain (n = 30, 15.4%) and repressor domain (n = 36, 18.4%). Clinical manifestations were as follows: enteropathy (n = 191, 97.9%), skin manifestations (n = 121, 62.1%), endocrinopathy (n = 104, 53.3%), hematologic abnormalities (n = 75, 38.5%), infections (n = 78, 40.0%), other immune-related complications (n = 43, 22.1%), and renal involvement (n = 32, 16.4%). Enteropathic presentations (P = 0.017), eczema (P = 0.030), autoimmune hemolytic anemia (P = 0.022) and food allergy (P = 0.009) were associated with better survival, while thrombocytopenia (P = 0.034), septic shock (P = 0.045) and mutations affecting the repressor domain (P = 0.021), intron 7 (P = 0.033) or poly A sequence (P = 0.025) were associated with increased risk of death. Immunosuppressive therapy alone was significantly associated with increased cumulative survival compared to patients who received no treatment (P = 0.041). CONCLUSIONS: We report the most comprehensive summary of demographic and clinical profiles derived from a total of 195 IPEX patients with deleterious mutations in FOXP3. Analysis of our findings provides new insights into genotype/phenotype correlations, and clinical and genetic factors associated with increased risk of death and response to treatment strategies.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Doenças do Sistema Imunitário , Enteropatias , Poliendocrinopatias Autoimunes , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Enteropatias/imunologia , Enteropatias/patologia , Mutação , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/patologia , Síndrome , Linfócitos T Reguladores/imunologia
3.
Invest Ophthalmol Vis Sci ; 61(3): 11, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32176262

RESUMO

Purpose: To define remodeling of photoreceptor synaptic terminals and second-order retinal neurons in canine X-linked progressive retinal atrophy 1 caused by a five-nucleotide deletion in the RPGR exon ORF15. Methods: Retinas of normal and mutant dogs were used for gene expression, Western blot, and immunohistochemistry. Cell-specific markers were used to examine disease-dependent retinal remodeling. Results: In mutant retinas, a number of rod axon terminals retract into the outer nuclear layer. This neuritic atrophy preceded significant loss of rods and was evident early in disease. Rod bipolar and horizontal cell processes were found to extend into the outer nuclear layer, where they seemed to form contacts with the spherules of rod photoreceptors. No ectopic rewiring was observed. Because cytoskeletal reorganization was previously shown to underlie photoreceptor axon retraction, we examined normal and mutant retinas for expression of axon guidance receptors ROBO1 and ROBO2, which are known to regulate actin cytoskeleton dynamics. We found that the overall expression of both ROBO1 and ROBO2 is retained at the same level in premature and fully developed normal retinas. However, analysis of predisease and early disease retinas identified markedly decreased levels of ROBO1 in rod spherules compared with controls. In contrast, no differences in ROBO1 signals were noted in cone pedicles in normal and mutant retinas, where ROBO1 levels remained similarly low. Conclusions: Depletion of ROBO1 in rod synaptic terminals correlates with the remodeling of axonal and dendritic processes in the outer retina of dogs with X-linked progressive retinal atrophy 1 and may play a role in the retraction of rod axons.


Assuntos
Doenças do Cão/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Terminações Pré-Sinápticas/metabolismo , Receptores Imunológicos/metabolismo , Degeneração Retiniana/metabolismo , Animais , Orientação de Axônios/fisiologia , Axônios/patologia , Doenças do Cão/genética , Doenças do Cão/patologia , Cães , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Doenças Genéticas Ligadas ao Cromossomo X/veterinária , Microscopia Confocal , Proteínas do Tecido Nervoso/deficiência , Plasticidade Neuronal/fisiologia , Terminações Pré-Sinápticas/patologia , Receptores Imunológicos/deficiência , Retina/metabolismo , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Degeneração Retiniana/veterinária , Neurônios Retinianos/metabolismo , Neurônios Retinianos/patologia , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/patologia
4.
Neurol India ; 67(5): 1344-1346, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31744973

RESUMO

X-linked myopathy with excessive autophagy (XMEA) is a rare, slowly progressive muscle disease characterized by membrane-bound sarcoplasmic vacuoles distinct from other forms of myopathies with vacuoles. We report this rare condition in a 5-year-old boy with proximal muscle weakness and morphological evidence of autophagic vacuoles.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/patologia , Músculo Esquelético/patologia , Doenças Musculares/patologia , Pré-Escolar , Humanos , Masculino
5.
Genes (Basel) ; 10(10)2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658606

RESUMO

Phosphoglycerate kinase (PGK)1 deficiency is an X-linked inherited disease associated with different clinical presentations, sometimes as myopathic affectation without hemolytic anemia. We present a 40-year-old male with a mild psychomotor delay and mild mental retardation, who developed progressive exercise intolerance, cramps and sporadic episodes of rhabdomyolysis but no hematological features. A genetic study was carried out by a next-generation sequencing (NGS) panel of 32 genes associated with inherited metabolic myopathies. We identified a missense variant in the PGK1 gene c.1114G > A (p.Gly372Ser) located in the last nucleotide of exon 9. cDNA studies demonstrated abnormalities in mRNA splicing because this change abolishes the exon 9 donor site. This novel variant is the first variant associated with a myopathic form of PGK1 deficiency in the Spanish population.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Erros Inatos do Metabolismo/genética , Mutação de Sentido Incorreto , Fosfoglicerato Quinase/genética , Adulto , Células Cultivadas , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Erros Inatos do Metabolismo/patologia , Fosfoglicerato Quinase/deficiência , Fosfoglicerato Quinase/metabolismo , Processamento de RNA , Espanha
6.
Proc Natl Acad Sci U S A ; 116(30): 14961-14970, 2019 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-31296563

RESUMO

O-GlcNAc transferase (OGT) is an X-linked gene product that is essential for normal development of the vertebrate embryo. It catalyses the O-GlcNAc posttranslational modification of nucleocytoplasmic proteins and proteolytic maturation of the transcriptional coregulator Host cell factor 1 (HCF1). Recent studies have suggested that conservative missense mutations distal to the OGT catalytic domain lead to X-linked intellectual disability in boys, but it is not clear if this is through changes in the O-GlcNAc proteome, loss of protein-protein interactions, or misprocessing of HCF1. Here, we report an OGT catalytic domain missense mutation in monozygotic female twins (c. X:70779215 T > A, p. N567K) with intellectual disability that allows dissection of these effects. The patients show limited IQ with developmental delay and skewed X-inactivation. Molecular analyses revealed decreased OGT stability and disruption of the substrate binding site, resulting in loss of catalytic activity. Editing this mutation into the Drosophila genome results in global changes in the O-GlcNAc proteome, while in mouse embryonic stem cells it leads to loss of O-GlcNAcase and delayed differentiation down the neuronal lineage. These data imply that catalytic deficiency of OGT could contribute to X-linked intellectual disability.


Assuntos
Domínio Catalítico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/genética , Mutação com Perda de Função , N-Acetilglucosaminiltransferases/genética , Animais , Linhagem Celular , Drosophila , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Fator C1 de Célula Hospedeira/metabolismo , Humanos , Deficiência Intelectual/patologia , Camundongos , N-Acetilglucosaminiltransferases/química , N-Acetilglucosaminiltransferases/metabolismo , Neurogênese , Mutação Puntual , Gêmeos Monozigóticos
7.
J Pediatr Endocrinol Metab ; 32(8): 915-920, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31271558

RESUMO

Nephrogenic diabetes insipidus (NDI) is a rare disorder of the renal collecting tubules, characterized by an inability to concentrate urine due to an impaired response to arginine vasopressin (AVP), resulting in dilute urine and polyuria. Causes of NDI are heterogeneous and diagnosing congenital NDI (cNDI) in young infants is clinically challenging, as typical symptoms are often unappreciated or inconspicuous. Instead, young infants may present with non-specific signs such as vomiting, poor feeding, failure to thrive, unexplained fevers, irritability, constipation or diarrhea. We report a 37-day-old infant who presented with polyuria and severe hypernatremic dehydration that was unresponsive to vasopressin. The patient was treated with amiloride, indomethacin and hydrochlorothiazide. Genetic analysis revealed a novel contiguous deletion involving the entire AVPR2 gene and the last exon of the adjacent ARHGAP4 gene. A study of the family confirmed the carrier status in the mother. This case illustrates the importance of molecular testing in confirming the diagnosis in the index patient, as well as in identifying asymptomatic at-risk female carriers so that appropriate genetic counselling can be given for reproductive planning. All pediatric patients with suspected cNDI should undergo genetic analysis for a definitive diagnosis.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Diabetes Insípido Nefrogênico/genética , Diabetes Insípido Nefrogênico/patologia , Proteínas Ativadoras de GTPase/genética , Deleção de Genes , Doenças Genéticas Ligadas ao Cromossomo X/genética , Receptores de Vasopressinas/genética , Éxons , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Lactente , Masculino , Linhagem , Prognóstico
8.
J Pediatr Endocrinol Metab ; 32(8): 863-869, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31219797

RESUMO

Background X-linked adrenal hypoplasia congenita (AHC), due to mutations in the nuclear receptor superfamily 0, group B, member 1 (NR0B1)/dosage-sensitive sex reversal, AHC, critical region on the X chromosome, gene 1 (DAX1) gene, usually presents with a salt-wasting adrenal crisis in infancy and hypogonadotropic hypogonadism (HH) in adolescents. Genetic reports in the literature from patients of diverse ethnicity are limited. We describe the atypical clinical characteristics and molecular genetic results in six Indian patients. Methods Both exons and flanking intronic sequences of the NR0B1 gene were amplified and sequenced in five patients. In the sixth patient, suspected to have a large deletion, multiplex ligation-dependent probe amplification (MLPA) and chromosomal microarray analysis were performed. Results Sequencing revealed three novel mutations: a nonsense mutation (c.776C > A), a deletion (c.298del), both causing loss of domains which are highly conserved among nuclear receptor families, and a missense mutation (c.1112T > C). In-silico analysis by structure-based protein modeling predicted a de-stabilizing effect of the novel missense mutation. Two previously reported mutations were seen in patients with atypical manifestations such as late-onset adrenal insufficiency and precocious puberty. One patient had a 7.15-Mb contiguous deletion involving the NR0B1, Duchenne muscular dystrophy (DMD), glycerol kinase (GK) and melanoma antigen, family B, 16 (MAGEB16) genes. Conclusions Our report emphasizes the wide clinical spectrum of AHC, including rare manifestations, and enumerates unique mutations in the NR0B1 gene.


Assuntos
Insuficiência Adrenal/genética , Insuficiência Adrenal/patologia , Receptor Nuclear Órfão DAX-1/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Mutação , Adulto , Criança , Análise Mutacional de DNA , Feminino , Seguimentos , Humanos , Índia , Lactente , Recém-Nascido , Masculino , Linhagem , Prognóstico , Adulto Jovem
9.
Proc Natl Acad Sci U S A ; 116(26): 12952-12957, 2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31189594

RESUMO

T cell-independent (TI) B cell response is critical for the early protection against pathogen invasion. The regulation and activation of Bruton's tyrosine kinase (Btk) is known as a pivotal step of B cell antigen receptor (BCR) signaling in TI humoral immunity, as observed in patients with X-linked agammaglobulinemia (XLA) experiencing a high incidence of encapsulated bacterial infections. However, key questions remain as to whether a well-established canonical BCR signaling pathway is sufficient to regulate the activity of Btk. Here, we find that inositol hexakisphosphate (InsP6) acts as a physiological regulator of Btk in BCR signaling. Absence of higher order inositol phosphates (InsPs), inositol polyphosphates, leads to an inability to mount immune response against TI antigens. Interestingly, the significance of InsP6-mediated Btk regulation is more prominent in IgM+ plasma cells. Hence, the present study identifies higher order InsPs as principal components of B cell activation upon TI antigen stimulation and presents a mechanism for InsP-mediated regulation of the BCR signaling.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Agamaglobulinemia/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Imunidade Humoral , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Ácido Fítico/imunologia , Tirosina Quinase da Agamaglobulinemia/imunologia , Agamaglobulinemia/genética , Agamaglobulinemia/patologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Modelos Animais de Doenças , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Camundongos , Camundongos Transgênicos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Ácido Fítico/metabolismo , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/imunologia
10.
Curr Opin Neurol ; 32(4): 604-609, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31116117

RESUMO

PURPOSE OF REVIEW: Our understanding of X-Linked Dystonia-Parkinsonism (XDP) has advanced considerably in recent years because of a wealth of new data describing its genetic basis, cellular phenotypes, neuroimaging features, and response to deep brain stimulation (DBS). This review provides a concise summary of these studies. RECENT FINDINGS: XDP is associated with a SINE-VNTR-Alu (SVA)-type retrotransposon insertion within the TAF1 gene. This element includes a hexameric DNA repeat expansion, (CCCTCT)n, the length of which varies among patients and is inversely correlated to age of disease onset. In cell models, the SVA alters TAF1 splicing and reduces levels of full-length transcript. Neuroimaging data have confirmed previous neuropathology studies that XDP involves a progressive striatal atrophy, while further detecting functional alterations in additional brain regions. In patients exhibiting features of both dystonia and parkinsonism, pallidal DBS has resulted in rapid improvement of hyperkinetic movements, but effects on hypokinetic features have been inconsistent. SUMMARY: The discovery that XDP is linked to a polymorphic hexameric sequence suggests that it could share mechanisms with other DNA repeat disorders, whereas the transcriptional defect in cell models raises the possibility that strategies to correct TAF1 splicing could provide therapeutic benefit.


Assuntos
Encéfalo/patologia , Expansão das Repetições de DNA , Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Encéfalo/diagnóstico por imagem , Estimulação Encefálica Profunda/métodos , Distúrbios Distônicos/diagnóstico por imagem , Distúrbios Distônicos/patologia , Distúrbios Distônicos/terapia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos
11.
Am J Hum Genet ; 104(5): 914-924, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982611

RESUMO

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506∗ and p.Glu496∗ were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.


Assuntos
Surdez/congênito , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Variação Genética , Glipicanas/genética , Deformidades Congênitas das Extremidades Inferiores/genética , Deformidades Congênitas das Extremidades Inferiores/patologia , Adulto , Criança , Pré-Escolar , Surdez/genética , Surdez/patologia , Feminino , Humanos , Lactente , Masculino , Linhagem , Fenótipo , Adulto Jovem
12.
Mol Med Rep ; 19(5): 4419-4424, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942463

RESUMO

Nance­Horan syndrome (NHS) is a rare X­linked disorder with various clinical manifestations. The present study aimed to identify the pathogenic mutation causing NHS in a three­generation Chinese family with 4 individuals presenting primarily with congenital cataracts. The genomic DNA of 5 individuals was collected, and family history and clinical information were recorded. Whole exome sequencing was performed on the proband, and candidate mutations were filtered by a series of screening processes and validated by Sanger sequencing. The identified pathogenic mutation was confirmed by co­segregation analysis. Finally, a novel frameshift mutation (NM_001291867.1: c.302dupA; p.Ala102fs) was identified in the NHS actin remodeling regulator (NHS) gene, which co­segregated with congenital cataracts in this family. Carrier females exhibited similar but milder clinical symptoms compared with the affected male. These clinical symptoms were consistent with the phenotypic features of the NHS­associated disease, NHS. In summary, the present study identified a novel NHS mutation in a Chinese family with atypical NHS; the results broaden the known pathogenic mutation spectrum of NHS and will aid in the genetic counseling of patients with NHS. The data from the present study also suggest that genetic analysis may be required for the diagnosis of this disease.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Catarata/congênito , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas Nucleares/genética , Anormalidades Dentárias/genética , Adulto , Catarata/genética , Catarata/patologia , Pré-Escolar , Feminino , Mutação da Fase de Leitura , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Linhagem , Anormalidades Dentárias/patologia , Sequenciamento Completo do Exoma
13.
Am J Hum Genet ; 104(5): 957-967, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31006512

RESUMO

Replicating the human genome efficiently and accurately is a daunting challenge involving the duplication of upward of three billion base pairs. At the core of the complex machinery that achieves this task are three members of the B family of DNA polymerases: DNA polymerases α, δ, and ε. Collectively these multimeric polymerases ensure DNA replication proceeds at optimal rates approaching 2 × 103 nucleotides/min with an error rate of less than one per million nucleotides polymerized. The majority of DNA replication of undamaged DNA is conducted by DNA polymerases δ and ε. The DNA polymerase α-primase complex performs limited synthesis to initiate the replication process, along with Okazaki-fragment synthesis on the discontinuous lagging strand. An increasing number of human disorders caused by defects in different components of the DNA-replication apparatus have been described to date. These are clinically diverse and involve a wide range of features, including variable combinations of growth delay, immunodeficiency, endocrine insufficiencies, lipodystrophy, and cancer predisposition. Here, by using various complementary approaches, including classical linkage analysis, targeted next-generation sequencing, and whole-exome sequencing, we describe distinct missense and splice-impacting mutations in POLA1 in five unrelated families presenting with an X-linked syndrome involving intellectual disability, proportionate short stature, microcephaly, and hypogonadism. POLA1 encodes the p180 catalytic subunit of DNA polymerase α-primase. A range of replicative impairments could be demonstrated in lymphoblastoid cell lines derived from affected individuals. Our findings describe the presentation of pathogenic mutations in a catalytic component of a B family DNA polymerase member, DNA polymerase α.


Assuntos
DNA Polimerase I/genética , DNA Primase/genética , Doenças Genéticas Ligadas ao Cromossomo X/etiologia , Transtornos do Crescimento/etiologia , Hipogonadismo/etiologia , Deficiência Intelectual/etiologia , Microcefalia/etiologia , Mutação , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Genótipo , Transtornos do Crescimento/patologia , Humanos , Hipogonadismo/patologia , Lactente , Deficiência Intelectual/patologia , Masculino , Microcefalia/patologia , Pessoa de Meia-Idade , Linhagem , Sequenciamento Completo do Exoma
14.
Int J Mol Sci ; 20(6)2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30917587

RESUMO

X-linked retinitis pigmentosa (XLRP) is a type of severe retinal dystrophy, and female carriers of XLRP demonstrate markedly variable clinical severity. In this study, we aimed to elucidate the clinical findings of male patients with and female carriers of XLRP in a Japanese cohort and demonstrate the genetic contribution. Twelve unrelated families (13 male patients, 15 female carriers) harboring pathogenic mutations in RPGR or RP2 were included, and comprehensive ophthalmic examinations were performed. To identify potential pathogenic mutations, targeted next-generation sequencing was employed. Consequently, we identified 11 pathogenic mutations, of which five were novel. Six and five mutations were detected in RPGR and RP2, respectively. Only one mutation was detected in ORF15. Affected male patients with RP2 mutations tended to have lower visual function than those with RPGR mutations. Female carriers demonstrated varying visual acuities and visual fields. Among the female carriers, 92% had electroretinographical abnormalities and 63% had a radial autofluorescent pattern, and the carriers who had higher myopia showed worse visual acuity and more severe retinal degeneration. Our results expand the knowledge of the clinical phenotypes of male patients with and female carriers of XLRP and suggest the possibility that RP2 mutations are relatively highly prevalent in Japan.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Retinite Pigmentosa/genética , Adolescente , Adulto , Proteínas do Olho/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Heterozigoto , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Mutação , Miopia/epidemiologia , Linhagem , Degeneração Retiniana/epidemiologia , Retinite Pigmentosa/epidemiologia , Retinite Pigmentosa/patologia , Acuidade Visual , Campos Visuais
16.
Nat Rev Endocrinol ; 15(5): 299-311, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30842651

RESUMO

Overgrowth syndromes are a heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features, such as visceromegaly, macrocephaly and a large range of various symptoms. These syndromes are caused by either genetic or epigenetic anomalies affecting factors involved in cell proliferation and/or the regulation of epigenetic markers. Some of these conditions are associated with neurological anomalies, such as cognitive impairment or autism. Overgrowth syndromes are frequently associated with an increased risk of cancer (embryonic tumours during infancy or carcinomas during adulthood), but with a highly variable prevalence. Given this risk, syndrome-specific tumour screening protocols have recently been established for some of these conditions. Certain specific clinical traits make it possible to discriminate between different syndromes and orient molecular explorations to determine which molecular tests to conduct, despite the syndromes having overlapping clinical features. Recent advances in molecular techniques using next-generation sequencing approaches have increased the number of patients with an identified molecular defect (especially patients with segmental overgrowth). This Review discusses the clinical and molecular diagnosis, tumour risk and recommendations for tumour screening for the most prevalent generalized and segmental overgrowth syndromes.


Assuntos
Neoplasias/epidemiologia , Neoplasias/genética , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/epidemiologia , Gigantismo/genética , Gigantismo/patologia , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Megalencefalia/epidemiologia , Megalencefalia/genética , Megalencefalia/patologia , Neoplasias/patologia , Gravidez , Fatores de Risco , Síndrome de Sotos/epidemiologia , Síndrome de Sotos/genética , Síndrome de Sotos/patologia , Síndrome
17.
Mol Genet Genomic Med ; 7(5): e647, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30883042

RESUMO

BACKGROUND: Alport syndrome is an inherited renal disease caused by mutations in COL4A3, COL4A4, or COL4A5 genes. Coexisting mutations in either two of the three genes in Alport patients have been reported recently. However, the effect of heterozygous mutations in COL4A3 or COL4A4 genes in X-linked Alport syndrome (XLAS) patients is unclear. METHODS: Using targeted next-generation sequencing, six unrelated Chinese children were identified to have a combination of a pathogenic variant in COL4A5 and a heterozygous mutation in COL4A3 or COL4A4. They were three males and three females. Another three XLAS males each with only one pathogenic variant in COL4A5 were included. The clinical data were analyzed and compared between the males in two groups (group 1, males with a pathogenic variant in COL4A5 and a heterozygous pathogenic variant in COL4A3 or COL4A4; group 2, males with only one pathogenic variant in COL4A5). RESULTS: Patients with XLAS who also had heterozygous pathogenic COL4A3 or COL4A4 variants accounted for 1% of Alport syndrome. In this study, three children showed coexisting pathogenic variants in COL4A5 and COL4A3. Two children showed pathogenic variants in COL4A5 and COL4A4. One child had pathogenic variants in the three COL4A3-5 genes, in which the pathogenic variant in COL4A5 was de novo and the pathogenic variants in COL4A4 and COL4A3 were inherited independently (in trans). The site and type of mutations in COL4A5 were similar between the two groups. It was revealed that males in group 1 presented more severe proteinuria than males in group 2 (p < 0.05). CONCLUSION: The present study provides further evidence for complicated genotype in Alport syndrome. For the first time, we reported a case with three pathogenic variants in COL4A5, COL4A3, and COL4A4 genes. Moreover, we found that heterozygous pathogenic COL4A3 or COL4A4 variants are likely to make XLAS disease more serious.


Assuntos
Autoantígenos/genética , Colágeno Tipo IV/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Heterozigoto , Nefrite Hereditária/genética , Criança , Pré-Escolar , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Masculino , Nefrite Hereditária/patologia , Fenótipo
20.
Am J Med Genet A ; 179(4): 650-654, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30737907

RESUMO

The AMME syndrome defined as the combination of Alport syndrome, intellectual disability, midface hypoplasia, and elliptocytosis (AMME) is known to be a contiguous gene syndrome associated with microdeletions in the region Xq22.3q23. Recently, using exome sequencing, missense pathogenic variants in AMMECR1 have been associated with intellectual disability, midface hypoplasia, and elliptocytosis. In these cases, AMMECR1 gene appears to be responsible for most of the clinical features of the AMME syndrome except for Alport syndrome. In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array-CGH involving TMEM164 and AMMECR1 genes and SNORD96B small nucleolar RNA for one patient, inherited from their mothers. These original cases further confirm that most specific AMME features are ascribed to AMMECR1 haploinsufficiency. These cases reporting the smallest microdeletions encompassing AMMECR1 gene provide new evidence for involvement of AMMECR1 in the AMME phenotype and permit to discuss a phenotype related to AMMECR1 haploinsufficiency: developmental delay/intellectual deficiency, midface hypoplasia, midline defect, deafness, and short stature.


Assuntos
Deleção Cromossômica , Cromossomos Humanos X/genética , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Eliptocitose Hereditária/genética , Eliptocitose Hereditária/patologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Proteínas de Membrana/genética , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Proteínas/genética , Criança , Humanos , Masculino , Prognóstico
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