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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 897-900, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515785

RESUMO

OBJECTIVE: To explore the genetic basis for a case of recurrent fetal congenital hydrocephalus. METHODS: Next-generation sequencing was carried out for the fetus, the gravida and two of her sisters. RESULTS: The fetus was found to harbor a c.1765T>C (p.Tyr589His) mutation in exon 14 of the L1CAM gene, which was derived from the gravida. CONCLUSION: Male fetuses with recurrent hydrocephalus should be subjected to testing of the L1CAM gene to facilitate genetic counseling and prenatal diagnosis.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Hidrocefalia/genética , Molécula L1 de Adesão de Célula Nervosa/genética , Análise Mutacional de DNA , Feminino , Feto , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Hidrocefalia/diagnóstico , Masculino , Mutação , Linhagem , Gravidez
3.
An Bras Dermatol ; 94(3): 341-343, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31365666

RESUMO

CHILD syndrome (Congenital Hemidysplasia, Ichthyosiform erythroderma, Limb Defects) is a rare X-linked dominant disease. The authors report a 2-month-old patient presenting with typical features of CHILD syndrome that was treated with a topical solution containing cholesterol and lovastatin, with complete clearance of her CHILD nevus. The changes in skin lipid metabolism that explain the CHILD ichthyosiform nevus and their correction through topical application of cholesterol and lovastatin are discussed.


Assuntos
Anormalidades Múltiplas/tratamento farmacológico , Anticolesterolemiantes/administração & dosagem , Colesterol/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Eritrodermia Ictiosiforme Congênita/tratamento farmacológico , Deformidades Congênitas dos Membros/tratamento farmacológico , Lovastatina/administração & dosagem , Anormalidades Múltiplas/genética , Administração Tópica , Colesterol/biossíntese , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Eritrodermia Ictiosiforme Congênita/genética , Lactente , Deformidades Congênitas dos Membros/genética , Doenças Metabólicas/genética
4.
Pan Afr Med J ; 32: 210, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31312322

RESUMO

Disorders of water balance are a disease commonly encountered in our clinical practice. Analysis of vasopressin receptor type II (V2R) is essential to understand the physiology of water balance and it is used as a biological prototype of G protein-coupled receptors (GPCRs). Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a syndrome of inappropriate antidiuretic hormone secretion (SIADH) with low plasmatic vasopressin. The evidence on the role of V2 receptor and of aquaporin (AQP) in the mechanism of action for antidiuretic hormone (ADH) was based on the identification of protein gene mutations in patients with nephrogenic diabetes insipidus and NSIAD syndrome. V2R activating mutations were found in patients with NSIAD, contrasting with the numerous V2R inactivating mutations related to X-linked mutations described in patients with nephrogenic diabetes insipidus.


Assuntos
Diabetes Insípido Nefrogênico/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Síndrome de Secreção Inadequada de HAD/fisiopatologia , Receptores de Vasopressinas/genética , Aquaporinas/metabolismo , Diabetes Insípido Nefrogênico/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Síndrome de Secreção Inadequada de HAD/genética , Mutação , Neurofisinas/metabolismo , Precursores de Proteínas/metabolismo , Receptores de Vasopressinas/metabolismo , Vasopressinas/sangue , Vasopressinas/metabolismo
6.
Cytogenet Genome Res ; 158(2): 56-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31158835

RESUMO

SHOX resides in the short arm pseudoautosomal region (PAR1) of the sex chromosomes and escapes X inactivation. SHOX haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). A substantial percentage of cases with SHOX haploinsufficiency arise from pseudoautosomal copy number variations (CNVs) involving putative enhancer regions of SHOX. Our previous study using peripheral blood samples showed that some CpG dinucleotides adjacent to SHOX exon 1 were hypomethylated in a healthy woman and methylated in a woman with gross X chromosomal rearrangements. However, it remains unknown whether submicroscopic pseudoautosomal CNVs cause aberrant DNA methylation of SHOX-flanking CpG islands. In this study, we examined the DNA methylation status of SHOX-flanking CpG islands in 50 healthy individuals and 10 ISS/LWD patients with pseudoautosomal CNVs. In silico analysis detected 3 CpG islands within the 20-kb region from the translation start site of SHOX. Pyrosequencing and bisulfite sequencing of genomic DNA samples revealed that these CpG islands were barely methylated in peripheral blood cells and cultured chondrocytes of healthy individuals, as well as in peripheral blood cells of ISS/LWD patients with pseudoautosomal CNVs. These results, in conjunction with our previous findings, indicate that the DNA methylation status of SHOX-flanking CpG islands can be affected by gross X-chromosomal abnormalities, but not by submicroscopic CNVs in PAR1. Such CNVs likely disturb SHOX expression through DNA methylation-independent mechanisms, which need to be determined in future studies.


Assuntos
Metilação de DNA , Doenças Genéticas Ligadas ao Cromossomo X/genética , Transtornos do Crescimento/genética , Osteocondrodisplasias/genética , Proteína de Homoeobox de Baixa Estatura/genética , Adolescente , Adulto , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Condrócitos , Ilhas de CpG , Variações do Número de Cópias de DNA , Feminino , Humanos , Análise de Sequência de DNA
7.
An Acad Bras Cienc ; 91(2): e20180945, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31241704

RESUMO

DNA methylation is essential for spatiotemporally-regulated gene expression in embryonic development. TBX22 (Chr X: 107667964-107688978) functioning as a transcriptional repressor affects DNA binding, sumoylation, and transcriptional repression associated with X-linked cleft palate. This study aimed to explore the relationship and potential mechanism between TBX22 exon 5 methylation and palatal shelf fusion induced by all-trans retinoic acid (ATRA). We performed DNA methylation profiling, using MethylRAD-seq, after high throughput sequencing of mouse embryos from control (n=9) and ATRA-treated (to induce cleft palate, n=9) C57BL/6J mice at embryonic gestation days(E) 13.5, 14.5 and 16.5. TBX22 exon 5 was hyper-methylated at the CpG site at E13.5 (P=0.025, log2FC=1.5) and E14.5 (P=0.011, log2FC:1.5) in ATRA-treated, whereas methylation TBX22 exon 5 at the CpG site was not significantly different at E16.5 (P=0.808, log2FC=-0.2) between control and ATRA-treated. MSP results showed a similar trend consistent with the MethylRAD-seq results. qPCR showed the change in TBX22 exon 5 expression level negatively correlated with its TBX22 exon 5 methylation level. These results indicate that changes in TBX22 exon 5 methylation might play an important regulatory role during palatal shelf fusion, and may enlighten the development of novel epigenetic biomarkers in the treatment of CP in the future.


Assuntos
Fissura Palatina/embriologia , Desenvolvimento Embrionário/genética , Éxons/genética , Doenças Genéticas Ligadas ao Cromossomo X/embriologia , Proteínas com Domínio T/genética , Animais , Fissura Palatina/genética , Modelos Animais de Doenças , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/genética , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Gravidez
8.
BMC Med Genet ; 20(1): 70, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053099

RESUMO

BACKGROUND: X-linked spondyloepiphyseal dysplasia tarda (SEDT-XL) is a skeletal disorder characterized by defective structures of vertebral bodies and/or of epiphyses of the long bones, resulting in moderately short stature and early joint degeneration. TRAPPC2 gene, which is important for collagen secretion, has been reported as causative for SEDT-XL. CASE PRESENTATION: Here, we report two variants of TRAPPC2 gene of SEDT-XL patients, a missense variant of start codon, c.1A > T, and a deletion variant, c.40delG. To understand molecular consequence of the variants, we establish an in vitro gene expression assay system and demonstrate that both mutated genes are transcribed, but are not properly translated, indicative of the pathogenic nature of those TRAPPC2 variants. CONCLUSIONS: In the current study, we provide additional experimental data showing that loss-of-function TRAPPC2 variants are probably causative for SEDT-XL phenotype. These findings further contribute to the understanding the clinical picture related to TRAPPC2 gene.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas de Membrana Transportadoras/genética , Osteocondrodisplasias/genética , Fatores de Transcrição/genética , Adolescente , Humanos , Masculino , Pessoa de Meia-Idade
9.
Gene ; 707: 86-92, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31071385

RESUMO

Retinitis pigmentosa (RP) is the most common form of inherited retinal degenerative diseases. X-linked RP accounts for nearly 15% of all RP cases. In this study, we identified a novel RP2 missense mutation Q158P in a Chinese XLRP family. The RP2 Q158P mutation located in the RP2 TBCC domain and obviously destabilized RP2 protein in ARPE-19 cells. The proteasome inhibitor MG132 could restore the RP2 Q158P protein levels. Meanwhile, lower doses of bortezomib and carfilzomib, another two proteasome inhibitors that have been approved in multiple myeloma clinical therapy, also could rescue the RP2 Q158P protein levels. The ubiquitination of RP2 Q158P protein obviously increased when compared with wild type RP2 protein. Our findings broadened the spectrum of RP2 mutations and may contribute a better understanding of the molecular mechanism of XLRP.


Assuntos
Proteínas do Olho/química , Proteínas do Olho/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/química , Proteínas de Membrana/genética , Mutação de Sentido Incorreto , Retinite Pigmentosa/genética , Linhagem Celular , China , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Modelos Moleculares , Linhagem , Domínios Proteicos , Estabilidade Proteica , Análise de Sequência de DNA
10.
Genet Test Mol Biomarkers ; 23(6): 423-427, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31063410

RESUMO

Aim: The aim of this study was to report a novel POU Class 3 Homeobox 4 (POU3F4) variant and to provide further guidance on genetic counseling for incomplete partition (IP) type III families in the Korean population by showing two new contrasting cases in terms of genotypes and inheritance. Materials and Methods: Two consecutively recruited hearing-impaired probands with seemingly nonsyndromic features and their biological mothers were included in this study. Sanger sequencing and quantitative polymerase chain reaction (PCR) assays were performed for POU3F4. Results: A novel frameshift variant of POU3F4, c.852delC (p.Ile285Serfs*3), was identified in one of the patients. This mutation is predicted to truncate the protein within the POU homeodomain, resulting in the complete loss of the last nucleus localization signal. The proband's biological mother was also shown to be a carrier of this c.852delC (p.Ile285Serfs*3) mutant allele. A de novo genomic deletion on chromosome Xq21.2 was confirmed in another subject via quantitative PCR. This subject's biological mother, however, was not a carrier of this deletion. This indicates that the large upstream deletion of POU3F4 in the second proband occurred de novo. This finding is compatible with the previously proposed tendency for a high de novo rate of large genomic deletions involving the X-linked deafness-2 (DFNX2) locus. Conclusion: This study adds a novel, probably pathogenic POU3F4 truncation variant to the literature and provides guidance toward effective genetic counseling for IP III subjects based on more frequent de novo occurrence of POU3F4 deletions than POU3F4 point variants.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Perda Auditiva Neurossensorial/genética , Fatores do Domínio POU/genética , Adulto , Criança , Surdez/genética , Família , Feminino , Mutação da Fase de Leitura/genética , Aconselhamento Genético/métodos , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Genótipo , Perda Auditiva/genética , Perda Auditiva Neurossensorial/metabolismo , Humanos , Masculino , Mutação , Linhagem , República da Coreia
11.
J Genet ; 982019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30945684

RESUMO

Microduplications of the X chromosome are a rare cause of X-linked intellectual disability (XLID), a clinically and genetically heterogeneous spectrum of disorders. In the present study, a 950-kb Xp22.12 microduplication including the RPS6KA3 gene was detected in affected members of a family, including the proband (male), his mother and one maternal uncle. Four female carriers had major depression and one of them also had mild intellectual disability. The present and previous cases with overlapping microduplications suggest that Xp22.12 microduplications can be included in the neuropsychiatric copy number variations.


Assuntos
Cromossomos Humanos X/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Esquizofrenia/genética , Adulto , Duplicação Cromossômica , Variações do Número de Cópias de DNA , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Pessoa de Meia-Idade , Linhagem , Esquizofrenia/diagnóstico
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.
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
14.
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
15.
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.
Orphanet J Rare Dis ; 14(1): 58, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808384

RESUMO

BACKGROUND: X-linked hypophosphatemia (XLH) is an inherited disease of phosphate metabolism in which inactivating mutations of the Phosphate Regulating Endopeptidase Homolog, X-Linked (PHEX) gene lead to local and systemic effects including impaired growth, rickets, osteomalacia, bone abnormalities, bone pain, spontaneous dental abscesses, hearing difficulties, enthesopathy, osteoarthritis, and muscular dysfunction. Patients with XLH present with elevated levels of fibroblast growth factor 23 (FGF23), which is thought to mediate many of the aforementioned manifestations of the disease. Elevated FGF23 has also been observed in many other diseases of hypophosphatemia, and a range of animal models have been developed to study these diseases, yet the role of FGF23 in the pathophysiology of XLH is incompletely understood. METHODS: The role of FGF23 in the pathophysiology of XLH is here reviewed by describing what is known about phenotypes associated with various PHEX mutations, animal models of XLH, and non-nutritional diseases of hypophosphatemia, and by presenting molecular pathways that have been proposed to contribute to manifestations of XLH. RESULTS: The pathophysiology of XLH is complex, involving a range of molecular pathways that variously contribute to different manifestations of the disease. Hypophosphatemia due to elevated FGF23 is the most obvious contributor, however localised fluctuations in tissue non-specific alkaline phosphatase (TNAP), pyrophosphate, calcitriol and direct effects of FGF23 have been observed to be associated with certain manifestations. CONCLUSIONS: By describing what is known about these pathways, this review highlights key areas for future research that would contribute to the understanding and clinical treatment of non-nutritional diseases of hypophosphatemia, particularly XLH.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Hipofosfatemia/fisiopatologia , Animais , Fatores de Crescimento de Fibroblastos/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Hipofosfatemia/genética , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética
17.
Prog Mol Biol Transl Sci ; 161: 47-67, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30711029

RESUMO

X-linked acrogigantism (XLAG) is a recently described early-onset gigantism due to GPR101 duplication that induces growth hormone (GH) oversecretion. GPR101, which belongs to Family A rhodopsin-like family of G protein-coupled receptors, is predominantly expressed in hypothalamus and pituitary, suggesting that GPR101 might be important in regulating diverse functions such as energy balance and reproduction. Most mammalian GPR101s have extremely long third intracellular loops (ICL3); however, zebrafish GPR101 has a much shorter ICL3, but a longer C-terminus. GnRH-(1-5), a GnRH metabolite, can modulate the hypothalamus-pituitary-gonad axis and cancer cell migration via activating GPR101. GPR101 couples to both Gαs and Gαi proteins. GPR101 duplication has a causative role in XLAG, while GPR101 variants, especially c.924G>C (E308D), located at ICL3, are attributed to acromegaly. Some GPR101 mutations that are associated with a small proportion of pituitary tumors without GH oversecretion have also been identified recently. This chapter will summarize studies on GPR101, including its molecular cloning and tissue distribution, physiology, pharmacology, and pathophysiology.


Assuntos
Acromegalia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Gigantismo/genética , Receptores Acoplados a Proteínas-G/genética , Sequência de Aminoácidos , Humanos , Modelos Biológicos , Mutação/genética , Receptores Acoplados a Proteínas-G/química
18.
Immunity ; 50(2): 362-377.e6, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30709738

RESUMO

Regulatory T (Treg) cells maintain immune tolerance through the master transcription factor forkhead box P3 (FOXP3), which is crucial for Treg cell function and homeostasis. We identified an IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) syndrome patient with a FOXP3 mutation in the domain swap interface of the protein. Recapitulation of this Foxp3 variant in mice led to the development of an autoimmune syndrome consistent with an unrestrained T helper type 2 (Th2) immune response. Genomic analysis of Treg cells by RNA-sequencing, Foxp3 chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-sequencing), and H3K27ac-HiChIP revealed a specific de-repression of the Th2 transcriptional program leading to the generation of Th2-like Treg cells that were unable to suppress extrinsic Th2 cells. Th2-like Treg cells showed increased intra-chromosomal interactions in the Th2 locus, leading to type 2 cytokine production. These findings identify a direct role for Foxp3 in suppressing Th2-like Treg cells and implicate additional pathways that could be targeted to restrain Th2 trans-differentiated Treg cells.


Assuntos
Fatores de Transcrição Forkhead/imunologia , Mutação , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Criança , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th2/metabolismo
19.
Allergol. immunopatol ; 47(1): 24-31, ene.-feb. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-180767

RESUMO

Background: X-linked agammaglobulinemia (XLA) is characterized by absent or severely reduced B cells, low or undetectable immunoglobulin levels, and clinically by extracellular bacterial infections which mainly compromise the respiratory tract. We aimed to analyze the clinical, immunological and genetic characteristics of 22 male children with XLA. Methods: Twenty-two children with XLA from 12 unrelated families were enrolled in this study. Clinical and demographic features of patients, serum immunoglobulin levels, percentage of B cells and BTK gene mutations were reviewed retrospectively. Results: We identified 12 different mutations in 22 patients from 12 unrelated families. The most frequent type of mutation was premature stop codon (33.3%). Ten mutations had been reported previously including three missense mutations (c.1774T>C, c.1684C>T, c.83G>T), three premature stop codons (c.1558C>T, c.1573C>T, c.753G>A), two splice-site (c.683-1G>A, c.1567-12_1567-9delTTTG) and two small nucleotide deletions (c.902-904_delAAG, c.179_181delAGA). Two novel mutations of the BTK gene were also presented and included one splice-site mutation (c.391+1G>C) and one premature stop codon mutation (c.1243_1243delG). Six out of 12 mutations of the BTK gene were located in the SH1 domain, two in the PH domain, two in the SH3 domain and two in the SH2 domain. Three patients had a history of severe infection before diagnosis. We did not identify any correlation between severity of clinical symptoms and the genotype. Conclusions: Our results show that mutations in southeast Turkey could be different from those in the rest of the world and molecular genetic tests are an important tool for early confirmed diagnosis of XLA


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Assuntos
Humanos , Masculino , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Agamaglobulinemia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Genótipo , Mutação/genética , Agamaglobulinemia/fisiopatologia , Progressão da Doença , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Predisposição Genética para Doença
20.
BMC Med Genet ; 20(1): 5, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30616528

RESUMO

BACKGROUND: Infantile nystagmus (IN) is an oculomotor disorder that is characterized by conjugate involuntary, rapid and repetitive movement of the eyes. To date, the pathogenesis of IN remains unclear. Many patients show an X-linked inheritance pattern. In this study, we explored the mutation in the FERM domain-containing 7 (FRMD7) gene in a Chinese family with X-linked infantile nystagmus. METHODS: We conducted comprehensive ocular examinations and collected 5 ml of blood samples from members of a family with X-linked IN and 100 normal controls. Mutations in FRMD7 were identified by sequencing PCR products. RESULTS: We found a 7-bp deletion(c.823-829delACCCTAC) in the 9th exon of FRMD7 in a Chinese family with IN, which predicted a truncation of the protein. CONCLUSIONS: This study reported a novel mutation of the FRMD7 gene occurred in a Chinese family with IN, thus expanding the spectrum of FRMD7 mutations causing IN, and further confirming that the mutations of FRMD7 are the underlying molecular cause of IN.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Proteínas do Citoesqueleto/genética , Mutação da Fase de Leitura , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas de Membrana/genética , Nistagmo Congênito/genética , Adulto , Sequência de Bases , Criança , China , Análise Mutacional de DNA , Éxons/genética , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Humanos , Masculino , Nistagmo Congênito/fisiopatologia , Deleção de Sequência
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