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1.
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
2.
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
3.
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
4.
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
6.
J Mol Neurosci ; 67(3): 418-423, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30618027

RESUMO

In this report, we described a large Han-Chinese family which presents with various phenotypes from unaffected to manifested nystagmus in females. Infantile nystagmus (IN) is characterized by bilateral, involuntary, and periodic eyeball oscillation, occurring at birth or within the first 6 months. The most common inheritance pattern of IN is an X-linked form with incomplete penetrance among females, and the FERM domain containing 7 gene (FRMD7) is a main disease-causing gene. A combination of exome sequencing and Sanger sequencing, as well as detailed clinical examinations were performed on the Chinese IN family. An FRMD7 c.47T>C (p.Phe16Ser) variant was proposed as the disease-causing variant. Incomplete penetrance was found in females with the FRMD7 c.47T>C variant, and hemizygous male affected subjects presented more severe manifestations compared to heterozygous female affected subjects. These findings could enhance genetic counseling and antenatal diagnosis of IN.


Assuntos
Proteínas do Citoesqueleto/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas de Membrana/genética , Nistagmo Congênito/genética , Polimorfismo de Nucleotídeo Único , Adulto , Proteínas do Citoesqueleto/química , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Hemizigoto , Humanos , Masculino , Proteínas de Membrana/química , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Nistagmo Congênito/patologia , Linhagem , Penetrância
8.
Int J Mol Sci ; 19(7)2018 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-29958424

RESUMO

Biosynthesis of heme represents a complex process that involves multiple stages controlled by different enzymes. The first of these proteins is a pyridoxal 5′-phosphate (PLP)-dependent homodimeric enzyme, 5-aminolevulinate synthase (ALAS), that catalyzes the rate-limiting step in heme biosynthesis, the condensation of glycine with succinyl-CoA. Genetic mutations in human erythroid-specific ALAS (ALAS2) are associated with two inherited blood disorders, X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP). XLSA is caused by diminished ALAS2 activity leading to decreased ALA and heme syntheses and ultimately ineffective erythropoiesis, whereas XLPP results from “gain-of-function” ALAS2 mutations and consequent overproduction of protoporphyrin IX and increase in Zn2+-protoporphyrin levels. All XLPP-linked mutations affect the intrinsically disordered C-terminal tail of ALAS2. Our earlier molecular dynamics (MD) simulation-based analysis showed that the activity of ALAS2 could be regulated by the conformational flexibility of the active site loop whose structural features and dynamics could be changed due to mutations. We also revealed that the dynamic behavior of the two protomers of the ALAS2 dimer differed. However, how the structural dynamics of ALAS2 active site loop and C-terminal tail dynamics are related to each other and contribute to the homodimer asymmetry remained unanswered questions. In this study, we used bioinformatics and computational biology tools to evaluate the role(s) of the C-terminal tail dynamics in the structure and conformational dynamics of the murine ALAS2 homodimer active site loop. To assess the structural correlation between these two regions, we analyzed their structural displacements and determined their degree of correlation. Here, we report that the dynamics of ALAS2 active site loop is anti-correlated with the dynamics of the C-terminal tail and that this anti-correlation can represent a molecular basis for the functional and dynamic asymmetry of the ALAS2 homodimer.


Assuntos
5-Aminolevulinato Sintetase/química , Anemia Sideroblástica/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Heme/química , 5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/patologia , Animais , Domínio Catalítico , Biologia Computacional , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Heme/biossíntese , Heme/genética , Humanos , Camundongos , Simulação de Dinâmica Molecular , Mutação/genética , Multimerização Proteica/genética
9.
Proc Natl Acad Sci U S A ; 115(28): E6640-E6649, 2018 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-29946028

RESUMO

Endosomes have emerged as a central hub and pathogenic driver of Alzheimer's disease (AD). The earliest brain cytopathology in neurodegeneration, occurring decades before amyloid plaques and cognitive decline, is an expansion in the size and number of endosomal compartments. The strongest genetic risk factor for sporadic AD is the ε4 allele of Apolipoprotein E (ApoE4). Previous studies have shown that ApoE4 potentiates presymptomatic endosomal dysfunction and defective endocytic clearance of amyloid beta (Aß), although how these two pathways are linked at a cellular and mechanistic level has been unclear. Here, we show that aberrant endosomal acidification in ApoE4 astrocytes traps the low-density lipoprotein receptor-related protein (LRP1) within intracellular compartments, leading to loss of surface expression and Aß clearance. Pathological endosome acidification is caused by ε4 risk allele-selective down-regulation of the Na+/H+ exchanger isoform NHE6, which functions as a critical leak pathway for endosomal protons. In vivo, the NHE6 knockout (NHE6KO) mouse model showed elevated Aß in the brain, consistent with a causal effect. Increased nuclear translocation of histone deacetylase 4 (HDAC4) in ApoE4 astrocytes, compared with the nonpathogenic ApoE3 allele, suggested a mechanistic basis for transcriptional down-regulation of NHE6. HDAC inhibitors that restored NHE6 expression normalized ApoE4-specific defects in endosomal pH, LRP1 trafficking, and amyloid clearance. Thus, NHE6 is a downstream effector of ApoE4 and emerges as a promising therapeutic target in AD. These observations have prognostic implications for patients who have Christianson syndrome with loss of function mutations in NHE6 and exhibit prominent glial pathology and progressive hallmarks of neurodegeneration.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteína E4/metabolismo , Astrócitos/metabolismo , Endossomos/metabolismo , Epigênese Genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Apolipoproteína E4/genética , Astrócitos/patologia , Ataxia/tratamento farmacológico , Ataxia/genética , Ataxia/metabolismo , Ataxia/patologia , Endossomos/genética , Endossomos/patologia , Epilepsia/tratamento farmacológico , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patologia , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Camundongos , Camundongos Knockout , Microcefalia/tratamento farmacológico , Microcefalia/genética , Microcefalia/metabolismo , Microcefalia/patologia , Transtornos da Motilidade Ocular/tratamento farmacológico , Transtornos da Motilidade Ocular/genética , Transtornos da Motilidade Ocular/metabolismo , Transtornos da Motilidade Ocular/patologia , Receptores de LDL/genética , Receptores de LDL/metabolismo , Trocadores de Sódio-Hidrogênio/genética , Trocadores de Sódio-Hidrogênio/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
10.
Mol Vis ; 24: 326-339, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29769798

RESUMO

Purpose: The aim of this study was to identify the molecular genetic basis of cone-rod dystrophy in 18 unrelated families of Polish origin. Cone-rod dystrophy is one of the inherited retinal dystrophies, which constitute a highly heterogeneous group of disorders characterized by progressive dysfunction of photoreceptors and retinal pigment epithelium (RPE) cells. Methods: The study group was composed of four groups of patients representing different Mendelian inheritance of the disease: autosomal dominant (AD), autosomal recessive (AR), X-linked recessive (XL), and autosomal recessive or X-linked recessive (AR/XL). The combined molecular strategy included Sanger sequencing of the RPGR-ORF15 gene (three families with XL and three families with the AR/XL mode of inheritance), mutation-specific microarray analysis of the ABCA4 gene (five families with the AR mode of inheritance and two families with the AR/XL mode of inheritance), targeted next-generation sequencing (NGS) of inherited retinal disease-associated (IRD) genes (seven families with the AD mode of inheritance and five families with the AR mode of inheritance), and whole exome sequencing, performed in select families who had been mutation-negative in the analysis with the targeted NGS panel (one family with the AD mode of inheritance, one family with the AR mode of inheritance, and two families with the AR/XL mode of inheritance). Results: Based on this combined strategy, we managed to identify potentially causative variants in seven out of 18 families with CRD. Five of these variants are novel: c.3142_3143dupAA, p.(Glu1049Argfs*41) in the RPGR-ORF15 gene, two variants: c.1612delT, p.(Trp538Glyfs*15) and c.2389dupG, p.(Ile798Hisfs*20) in the PROM1 gene in one family, c.592A>C, p.(Ser198Arg) in the PRPH2 gene and the variant c.1691A>G, p.(Asp564Gly) in the ATF6 gene that we have already reported to be pathogenic. NGS on the IRD panel allowed the molecular basis of CRD to be identified in four out of 14 families with a total detection rate of 38%. WES allowed identification of the molecular genetic basis of CRD in one family. Conclusions: This is the first report on the spectrum of disease genes and pathogenic variants causing CRD in the Polish population. The study presents five novel variants identified in four genes and therefore, broadens the spectrum of probable pathogenic variants associated with CRD.


Assuntos
Antígeno AC133/genética , Transportadores de Cassetes de Ligação de ATP/genética , Fator 6 Ativador da Transcrição/genética , Transtornos Cromossômicos/genética , Distrofias de Cones e Bastonetes/genética , Proteínas do Olho/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Periferinas/genética , Adolescente , Adulto , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/patologia , Estudos de Coortes , Distrofias de Cones e Bastonetes/diagnóstico , Distrofias de Cones e Bastonetes/patologia , Feminino , Expressão Gênica , Genes Dominantes , Genes Recessivos , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Polônia , Polimorfismo Genético , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Análise de Sequência de DNA
12.
Histochem Cell Biol ; 149(6): 593-605, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29574488

RESUMO

The Simpson-Golabi-Behmel syndrome (SGBS) cell strain is widely considered to be a representative in vitro model of human subcutaneous white pre-adipocytes. These cells achieve a transient expression of classical brown markers, such as uncoupling protein 1, peaking at day 14 of differentiation and decreasing thereafter. Adipocyte browning process involves dynamic changes in lipid droplet (LD) dimension, in mitochondria morphology, and in the expression of brown-specific marker genes. This study analyzes SGBS transient phenotypic transformation by quantifying the heterogeneity of LDs, mitochondrial dynamics, and a panel of genes involved in adipocyte differentiation and browning. LDs at 21 days of differentiation were larger than in the previous stages, without any change in the number per cell. The expression of genes such as peroxisome peroxisome proliferator-activated receptor γ, leptin, and lipase E significantly raised from 0 to 21 days. Adiponectin was significantly upregulated at 14 days of differentiation. Brown-specific marker PR domain containing 16 was highly expressed at D0. The variability of mitochondrial shape and interconnectivity reflects differences in the relative rates of fusion and fission, resulting in a significant shift from a networked shape at D7 to a fragmented and swollen one at D14 and D21. The transient phenotype experienced by this cellular model should be considered whether used in studies involving the stimulation of adipocyte browning and could be an interesting human model to further elucidate the browning process in the absence of any stimulation.


Assuntos
Adipócitos/patologia , Arritmias Cardíacas/patologia , Diferenciação Celular , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Gigantismo/patologia , Cardiopatias Congênitas/patologia , Deficiência Intelectual/patologia , Adipócitos/metabolismo , Arritmias Cardíacas/metabolismo , Células Cultivadas , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Gigantismo/metabolismo , Cardiopatias Congênitas/metabolismo , Humanos , Deficiência Intelectual/metabolismo , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fenótipo
13.
PLoS One ; 13(2): e0193372, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29474464

RESUMO

Four full-sibling intact male Miniature Poodles were evaluated at 4-19 months of age. One was clinically normal and three were affected. All affected dogs were reluctant to exercise and had generalised muscle atrophy, a stiff gait and a markedly elevated serum creatine kinase activity. Two affected dogs also showed poor development, learning difficulties and episodes of abnormal behaviour. In these two dogs, investigations into forebrain structural and metabolic diseases were unremarkable; electromyography demonstrated fibrillation potentials and complex repetitive discharges in the infraspinatus, supraspinatus and epaxial muscles. Histopathological, immunohistochemical and immunoblotting analyses of muscle biopsies were consistent with dystrophin-deficient muscular dystrophy. DNA samples were obtained from all four full-sibling male Poodles, a healthy female littermate and the dam, which was clinically normal. Whole genome sequencing of one affected dog revealed a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene. The exact deletion breakpoints could not be experimentally ascertained, but we confirmed that this region was deleted in all affected males, but not in the unaffected dogs. Quantitative polymerase chain reaction confirmed all three affected males were hemizygous for the mutant X chromosome, while the wildtype chromosome was observed in the unaffected male littermate. The female littermate and the dam were both heterozygous for the mutant chromosome. Forty-four Miniature Poodles from the general population were screened for the mutation and were homozygous for the wildtype chromosome. The finding represents a naturally-occurring mutation causing dystrophin-deficient muscular dystrophy in the dog.


Assuntos
Doenças do Cão/genética , Doenças do Cão/fisiopatologia , Distrofina/deficiência , Distrofina/genética , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/fisiopatologia , Animais , Doenças do Cão/patologia , Doenças do Cão/terapia , Cães , Genes Recessivos , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Distrofia Muscular Animal/patologia , Distrofia Muscular Animal/terapia , Linhagem , Irmãos
14.
Scand J Immunol ; 87(3)2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29424453

RESUMO

X-linked agammaglobulinemia is a primary immunodeficiency disorder resulting from BTK gene mutations. There are many studies in the literature suggesting contradictory ideas about phenotype-genotype correlation. The aim of this study was to identify the mutations and clinical findings of patients with XLA in Turkey, to determine long-term complications related to the disease and to analyse the phenotype-genotype correlation. Thirty-two patients with XLA diagnosed between 1985 and 2016 in Pediatric Immunology Department of Hacettepe University Ihsan Dogramaci Children's Hospital were investigated. A clinical survey including clinical features of the patients was completed, and thirty-two patients from 26 different families were included in the study. Getting early diagnosis and regular assessment with imaging techniques seem to be the most important issues for improving the health status of the patients with XLA. Early molecular analysis gives chance for definitive diagnosis and genetic counselling, but not for predicting the clinical severity and prognosis.


Assuntos
Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Anticorpos/sangue , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas Tirosina Quinases/genética , Adolescente , Adulto , Tirosina Quinase da Agamaglobulinemia , Agamaglobulinemia/patologia , Infecções Bacterianas/imunologia , Criança , Pré-Escolar , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Lactente , Estudos Retrospectivos , Turquia , Adulto Jovem
15.
Retina ; 38(5): 1047-1057, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28376043

RESUMO

PURPOSE: To investigate the clinical features in carriers of X-linked retinitis pigmentosa, X-linked ocular albinism, and choroideremia (CHM) using multimodal imaging and to assess their diagnostic value in these three mosaic retinopathies. METHODS: We prospectively examined 14 carriers of 3 X-linked recessive disorders (X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM). Details of abnormalities of retinal morphology were evaluated using fundus photography, fundus autofluorescence (FAF) imaging, and spectral domain optical coherence tomography. RESULTS: In six X-linked retinitis pigmentosa carriers, fundus appearance varied from unremarkable to the presence of tapetal-like reflex and pigmentary changes. On FAF imaging, all carriers exhibited a bright radial reflex against a dark background. By spectral domain optical coherence tomography, loss of the ellipsoid zone in the macula was observed in 3 carriers (50%). Regarding the retinal laminar architecture, 4 carriers (66.7%) showed thinning of the outer nuclear layer and a dentate appearance of the outer plexiform layer. All five X-linked ocular albinism carriers showed a characteristic mud-splatter patterned fundus, dark radial streaks against a bright background on FAF imaging, and a normal-appearing retinal structure by spectral domain optical coherence tomography imaging. Two of the 3 CHM carriers (66.7%) showed a diffuse moth-eaten appearance of the fundus, and all 3 showed irregular hyper-FAF and hypo-FAF spots throughout the affected area. In the CHM carriers, the structural changes observed by spectral domain optical coherence tomography imaging were variable. CONCLUSION: Our findings in an Asian cohort suggest that FAF imaging is a practical diagnostic test for differentiating X-linked retinitis pigmentosa, X-linked ocular albinism, and CHM carriers. Wide-field FAF is an easy and helpful adjunct to testing for the correct diagnosis and identification of lyonization in carriers of these three mosaic retinopathies.


Assuntos
Albinismo Ocular/patologia , Coroideremia/patologia , Técnicas de Diagnóstico Oftalmológico , Triagem de Portadores Genéticos , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Retinite Pigmentosa/patologia , Adulto , Albinismo Ocular/diagnóstico por imagem , Criança , Pré-Escolar , Coroideremia/diagnóstico por imagem , Feminino , Angiofluoresceinografia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Estudos Prospectivos , Retinite Pigmentosa/diagnóstico por imagem , Tomografia de Coerência Óptica , Adulto Jovem
16.
J Clin Immunol ; 37(7): 727-731, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28856582

RESUMO

ᅟ: Helicobacter bilis is a commensal bacterium causing chronic hepatitis and colitis in mice. In humans, enterohepatic Helicobacter spp. are associated with chronic hepatobiliary diseases. PURPOSE: We aimed at understanding the microbial etiology in a patient with X-linked agammaglobulinemia presenting with suppurative cholangitis. METHODS: 16S rDNA PCR directly performed on a liver biopsy retrieved DNA of H. bilis. RESULTS: Clinical outcome resulted in the normalization of clinical and biological parameters under antibiotic treatment by a combination of ceftriaxone, metronidazole, and doxycyclin followed by a 2-week treatment with moxifloxacin and a 2-month treatment with azithromycin. CONCLUSION: In conclusion, these data suggest a specific clinical and microbiological approach in patients with humoral deficiency in order to detect H. bilis hepatobiliary diseases.


Assuntos
Agamaglobulinemia/microbiologia , Colangite/microbiologia , Doenças Genéticas Ligadas ao Cromossomo X/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter/genética , Agamaglobulinemia/tratamento farmacológico , Agamaglobulinemia/patologia , Antibacterianos/uso terapêutico , Colangite/tratamento farmacológico , Colangite/patologia , DNA Bacteriano/genética , DNA Ribossômico/genética , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/patologia , Humanos , Fígado/patologia , Masculino , Adulto Jovem
17.
Biochim Biophys Acta Mol Cell Res ; 1864(10): 1844-1854, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28760657

RESUMO

MID1/TRIM18 is a member of the TRIM family of ubiquitin E3 ligases characterized by the presence of a conserved RING-containing N-terminal tripartite motif. Mutations in the MID1 gene have been associated with the X-linked form of Opitz Syndrome, a developmental disorder characterized by midline defects and intellectual disability. The effect of MID1 E3 ligase activity within the cell and the role in the pathogenesis of the disease is still not completely unraveled. Here, we report BRAF35, a non-canonical HMG nuclear factor, as a novel MID1 substrate. MID1 is implicated in BRAF35 ubiquitination promoting atypical poly-ubiquitination via K6-, K27- and K29-linkages. We observed a partial co-localization of the two proteins within cytoplasmic bodies. We found that MID1 depletion alters BRAF35 localization in these structures and increases BRAF35 stability affecting its cytoplasmic abundance. Our data reveal a novel role for MID1 and for atypical ubiquitination in balancing BRAF35 presence, and likely its activity, within nuclear and cytoplasmic compartments.


Assuntos
Fissura Palatina/genética , Esôfago/anormalidades , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas de Grupo de Alta Mobilidade/genética , Hipertelorismo/genética , Hipospadia/genética , Proteínas dos Microtúbulos/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética , Sequência de Aminoácidos , Fissura Palatina/patologia , Citoplasma/enzimologia , Esôfago/patologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Hipertelorismo/patologia , Hipospadia/patologia , Proteínas dos Microtúbulos/metabolismo , Mutação , Proteínas Nucleares/metabolismo , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina/genética , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
18.
Prenat Diagn ; 37(10): 1040-1045, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28833278

RESUMO

OBJECTIVE: To identify the underlying genetic cause for recurrent intrauterine fetal death (IUFD) of males. METHODS: Whole genome sequencing was performed on DNA from five healthy obligatory carrier females and an unaffected male offspring of a multigenerational pedigree with recurrent second-trimester IUFD of males (n = 19). When documented, all deaths occurred at ≤20 weeks of gestation. Hydrops fetalis was diagnosed at death in the most recent case. RESULTS: Following variant filtering based on a recessive X-linked inheritance pattern, a rare FOXP3 frameshift mutation (p.D303fs*87) that results in a premature truncation of the protein was discovered. Sanger sequencing confirmed the mutation in the affected fetus. The FOXP3 gene encodes for a transcriptional regulator critical to the function of regulatory T cells. FOXP3 mutations are associated with immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome which exclusively affects males and may present with a potentially life-threatening complex autoimmune disorder in early childhood. CONCLUSIONS: Here, we demonstrate the utility of whole genome sequencing-based pedigree analysis to identify the genetic cause for recurrent IUFD when chromosome studies, including microarray analysis, are normal. Further studies are needed to determine the prevalence of FOXP3-mediated IUFD in males. © 2017 John Wiley & Sons, Ltd.


Assuntos
Morte Fetal/etiologia , Sequenciamento Completo do Genoma , DNA/análise , Diabetes Mellitus Tipo 1/congênito , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Diarreia/genética , Diarreia/patologia , Feminino , Fatores de Transcrição Forkhead/genética , Mutação da Fase de Leitura/genética , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Idade Gestacional , Humanos , Hidropisia Fetal/genética , Doenças do Sistema Imunitário/congênito , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Masculino , Linhagem , Gravidez , Segundo Trimestre da Gravidez
19.
PLoS One ; 12(6): e0178753, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28575130

RESUMO

Loss of Norrin signalling due to mutations in the Norrie disease pseudoglioma gene causes severe vascular defects in the retina, leading to visual impairment and ultimately blindness. While the emphasis of experimental work so far was on the developmental period, we focus here on disease mechanisms that induce progression into severe adult disease. The goal of this study was the comprehensive analysis of the long-term effects of the absence of Norrin on vascular homeostasis and retinal function. In a mouse model of Norrie disease retinal vascular morphology and integrity were studied by means of in vivo angiography; the vascular constituents were assessed in detailed histological analyses using quantitative retinal morphometry. Finally, electroretinographic analyses were performed to assess the retinal function in adult Norrin deficient animals. We could show that the primary developmental defects not only persisted but developed into further vascular abnormalities and microangiopathies. In particular, the overall vessel homeostasis, the vascular integrity, and also the cellular constituents of the vascular wall were affected in the adult Norrin deficient retina. Moreover, functional analyses indicated to persistent hypoxia in the neural retina which was suggested as one of the major driving forces of disease progression. In summary, our data provide evidence that the key to adult Norrie disease are ongoing vascular modifications, driven by the persistent hypoxic conditions, which are ineffective to compensate for the primary Norrin-dependent defects.


Assuntos
Cegueira/congênito , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Proteínas do Tecido Nervoso/deficiência , Doenças do Sistema Nervoso/patologia , Vasos Retinianos/patologia , Espasmos Infantis/patologia , Angiografia , Animais , Cegueira/diagnóstico por imagem , Cegueira/genética , Cegueira/patologia , Capilares/patologia , Hipóxia Celular , Modelos Animais de Doenças , Progressão da Doença , Eletrorretinografia , Proteínas do Olho/genética , Proteínas do Olho/fisiologia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico por imagem , Doenças Genéticas Ligadas ao Cromossomo X/genética , Lasers , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Patológica/etiologia , Neovascularização Patológica/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/genética , Oftalmoscopia/métodos , Degeneração Retiniana , Vasos Retinianos/diagnóstico por imagem , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/genética
20.
FEBS J ; 284(14): 2183-2193, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28548391

RESUMO

Mutations of human MID1 are associated with X-linked Opitz G Syndrome (XLOS), which is characterized by midline birth defects. XLOS-observed mutations within the MID1 B-box1 domain are associated with cleft lip/palate, wide-spaced eyes and hyperspadias. Three of the four XLOS-observed mutations in the B-box1 domain results in unfolding but the structural and functional effects of the P151L mutation is not characterized. Here, we demonstrate that the P151L mutation does not disrupt the overall tertiary structure of the B-box1 domain and the adjacent domains. In fact, MID1 E3 ligase activity is slightly enhanced. However, the P151L mutation disrupted the ability of MID1 to catalyze the poly-ubiquitination of alpha4, a novel regulator of PP2A. This observation is consistent with results observed with the other three structure-destabilizing B-box1 mutations in targeting alpha4 but not PP2A. Alpha4 is shown to bind and sequester the catalytic subunit of PP2A and protect it from MID1-mediated ubiquitination and as a result, an increase in alpha4 can contribute to an increase in PP2A, playing a greater role in midline development during embryogenesis.


Assuntos
Fissura Palatina/genética , Fissura Palatina/metabolismo , Esôfago/anormalidades , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Hipertelorismo/genética , Hipertelorismo/metabolismo , Hipospadia/genética , Hipospadia/metabolismo , Proteínas dos Microtúbulos/química , Proteínas dos Microtúbulos/metabolismo , Mutação , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Processamento de Proteína Pós-Traducional , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Fissura Palatina/patologia , Esôfago/metabolismo , Esôfago/patologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Hipertelorismo/patologia , Hipospadia/patologia , Proteínas dos Microtúbulos/genética , Proteínas dos Microtúbulos/ultraestrutura , Modelos Moleculares , Proteínas Nucleares/genética , Proteínas Nucleares/ultraestrutura , Domínios Proteicos , Proteína Fosfatase 2/metabolismo , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , Especificidade por Substrato , Fatores de Transcrição/genética , Fatores de Transcrição/ultraestrutura , Ubiquitinação
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