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1.
Int J Mol Sci ; 23(17)2022 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-36076925

RESUMO

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disease caused by heterozygous missense mutations within the gene encoding for the nuclear envelope protein transmembrane protein 43 (TMEM43). The disease is characterized by myocyte loss and fibro-fatty replacement, leading to life-threatening ventricular arrhythmias and sudden cardiac death. However, the role of TMEM43 in the pathogenesis of ACM remains poorly understood. In this study, we generated cardiomyocyte-restricted transgenic zebrafish lines that overexpress eGFP-linked full-length human wild-type (WT) TMEM43 and two genetic variants (c.1073C>T, p.S358L; c.332C>T, p.P111L) using the Tol2-system. Overexpression of WT and p.P111L-mutant TMEM43 was associated with transcriptional activation of the mTOR pathway and ribosome biogenesis, and resulted in enlarged hearts with cardiomyocyte hypertrophy. Intriguingly, mutant p.S358L TMEM43 was found to be unstable and partially redistributed into the cytoplasm in embryonic and adult hearts. Moreover, both TMEM43 variants displayed cardiac morphological defects at juvenile stages and ultrastructural changes within the myocardium, accompanied by dysregulated gene expression profiles in adulthood. Finally, CRISPR/Cas9 mutants demonstrated an age-dependent cardiac phenotype characterized by heart enlargement in adulthood. In conclusion, our findings suggest ultrastructural remodeling and transcriptomic alterations underlying the development of structural and functional cardiac defects in TMEM43-associated cardiomyopathy.


Assuntos
Displasia Arritmogênica Ventricular Direita , Adulto , Animais , Displasia Arritmogênica Ventricular Direita/genética , Heterozigoto , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação de Sentido Incorreto , Miocárdio/metabolismo , Peixe-Zebra/genética
2.
Am J Med Genet A ; 188(10): 2861-2868, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36097642

RESUMO

Spondylo-epi-metaphyseal dysplasias (SEMDs) are a clinically and genetically heterogeneous group of skeletal dysplasias characterized by short stature and abnormal modeling of the spine and long bones. A novel form of rhizomelic skeletal dysplasia, Ain-Naz type, associated with a homozygous variant in GNPNAT1 was recently identified. Herein, we report an Egyptian patient, offspring of consanguineous parents, who presented with a severe form of unclassified SEMD. Whole exome sequencing identified a novel homozygous variant in exon 3, c.77T>G, (p.Phe26Cys) in GNPNAT1, that was confirmed by Sanger sequencing and both parents were found to be heterozygous for the identified variant. Main features included severe short stature, rhizomelic limb shortening, and wide flared metaphysis. Short broad long bones, brachydactyly, delayed epiphyseal ossification of long bones, advanced bone age, and immunodeficiency were additional findings expanding the clinical phenotype described in the previously reported family. We conclude that variants in the GNPNAT1 gene cause an autosomal recessive form of SEMD resembling Desbuquois like dysplasia caused by PGM3, which is involved in the same pathway as GNPNAT1.


Assuntos
Nanismo , Osteocondrodisplasias , Nanismo/diagnóstico por imagem , Nanismo/genética , Glucosamina 6-Fosfato N-Acetiltransferase/genética , Heterozigoto , Humanos , Hiperplasia , Osteocondrodisplasias/genética , Fosfoglucomutase/genética , Sequenciamento Completo do Exoma
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(9): 979-982, 2022 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-36082569

RESUMO

OBJECTIVE: To explore the genetic basis for a neonate featuring developmental delay. METHODS: Clinical examination and laboratory tests were carried out for the patient. Peripheral venous blood samples of the proband and his parents were extracted and subjected to target capture next generation sequencing. Candidate variant was verified by Sanger sequencing. RESULTS: The patient, a four-month-old male, has presented with developmental delay and weakness of limbs. Genetic testing revealed that he had harbored a novel c.1432C>T variant of the TNPO3 gene, which was inherited from his mother. The nonsense variant has resulted in premature termination of protein translation and was predicted to be pathogenic by bioinformatics analysis. CONCLUSION: The heterozygous c.1432C>T variant of the TNPO3 gene probably underlay the limb-girdle muscular dystrophies form 1F in this patient. Above finding has enriched the variation spectrum of the TNPO3 gene.


Assuntos
Distrofia Muscular do Cíngulo dos Membros , Testes Genéticos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Fenótipo , beta Carioferinas/genética
4.
Med Sci (Paris) ; 38(8-9): 655-662, 2022.
Artigo em Francês | MEDLINE | ID: mdl-36094235

RESUMO

Pseudohypoparathyroidism (PHP) is an uncommon disorder which is characterized by end-organ PTH resistance. The genetic defect is located at the GNAS locus that encodes the alpha-subunit of the stimulatory G protein (Gαs) and several splice variants thereof. This complex locus undergoes parental specific methylation changes that result in tissue-specific silencing of the paternal allele. Heterozygous inactivating mutations that disrupt Gαs function or epigenetics changes that impair Gαs expression contribute to a wide clinical spectrum of the disease: PHP1A, PHP1B, osseous heteroplasia, osteodystrophy, obesity, intrauterine growth retardation… whose mechanisms at the molecular level remain unresolved.


Title: Pseudo-hypoparathyroïdie et ses variants - Un succès de la médecine translationnelle. Abstract: Les pseudohypoparathyroïdies (PHP) sont des maladies rares, caractérisées par une résistance à l'action rénale de la parathormone. Le défaut génétique est localisé au locus GNAS, qui code la sous-unité alpha stimulatrice des protéines G (Gαs). Ce locus est le siège de régulations complexes, épissage alternatif et empreinte parentale éteigant de façon tissu-spécifique l'expression de l'allèle paternel. Des mutations hétérozygotes perte de fonction, des épimutations responsables d'une perte d'expression sont associées à un large spectre pathologique : PHP1A, PHP1B, ossification hétérotopique, ostéodystophie, obésité, retard de croissance in utero, etc., dont les mécanismes restent encore incomplètement connus.


Assuntos
Cromograninas , Pseudo-Hipoparatireoidismo , Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Heterozigoto , Humanos , Pseudo-Hipoparatireoidismo/genética , Ciência Translacional Biomédica
5.
Turk J Pediatr ; 64(4): 741-746, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36082648

RESUMO

BACKGROUND: Monocarboxylate transporter 1 (MCT1) deficiency (MIM #616095) is a relatively new identified cause of recurrent ketoacidosis triggered by fasting or infections. MCT1 was first described in 2014 by van Hasselt et al. to result from both homozygous and heterozygous mutations in the SLC16A1 gene. Patients with homozygous mutations are known to have a more severe phenotype with developmental delay and epilepsy. Thirteen patients with MCT1 deficiency with ketoacidosis have been reported in the literature to date. CASE: We describe a developmentally normal male patient with heterozygous missense variation in the SLC16A1 gene. Our patient who presented with cyclic vomiting and ketoacidosis episodes was found to have a heterozygous c.303T > G (p.Ile101Met) missense mutation. CONCLUSIONS: It is crucial to take early preventive measures and to minimize the harmful effects of ketoacidotic episodes. MCT1 deficiency should be considered in the differential diagnosis of ketoacidosis in patients with normal SCOT and ACAT1 activities.


Assuntos
Cetose , Heterozigoto , Homozigoto , Humanos , Cetose/etiologia , Masculino , Mutação , Fenótipo
6.
Proc Natl Acad Sci U S A ; 119(37): e2203557119, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36067312

RESUMO

Developmental dysplasia of the hip (DDH) is one of the most common congenital skeletal malformations; however, its etiology remains unclear. Here, we conducted whole-exome sequencing in eight DDH families followed by targeted sequencing of 68 sporadic DDH patients. We identified likely pathogenic variants in the LRP1 (low-density lipoprotein receptor-related protein 1) gene in two families and seven unrelated patients. All patients harboring the LRP1 variants presented a typical DDH phenotype. The heterozygous Lrp1 knockout (KO) mouse (Lrp1+/-) showed phenotypes recapitulating the human DDH phenotypes, indicating Lrp1 loss of function causes DDH. Lrp1 knockin mice with a missense variant corresponding to a human variant identified in DDH (Lrp1R1783W) also presented DDH phenotypes, which were milder in heterozygotes and severer in homozygotes than those of the Lrp1 KO mouse. The timing of triradiate cartilage development was brought forward 1 or 2 wk earlier in the LRP-deficient mice, which leads to malformation of the acetabulum and femoral head. Furthermore, Lrp1 deficiency caused a significant decrease of chondrogenic ability in vitro. During the chondrogenic induction of mice bone marrow stem cells and ATDC5 (an inducible chondrogenic cell line), Lrp1 deficiency caused decreased autophagy levels with significant ß-catenin up-regulation and suppression of chondrocyte marker genes. The expression of chondrocyte markers was rescued by PNU-74654 (a ß-catenin antagonist) in an shRNA-Lrp1-expressed ATDC5 cell. Our study reveals a critical role of LRP1 in the etiology and pathogenesis of DDH, opening an avenue for its treatment.


Assuntos
Autofagia , Condrócitos , Displasia do Desenvolvimento do Quadril , Heterozigoto , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Animais , Autofagia/genética , Condrócitos/metabolismo , Condrócitos/patologia , Displasia do Desenvolvimento do Quadril/genética , Displasia do Desenvolvimento do Quadril/patologia , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Camundongos , Camundongos Knockout , beta Catenina/metabolismo
7.
Genes (Basel) ; 13(8)2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-36011297

RESUMO

Obtaining a full short tandem repeat (STR) profile from a low template DNA (LT-DNA) still presents a challenge for conventional methods due to significant stochastic effects and polymerase slippage. A novel amplification method with a lower cost and higher accuracy is required to improve the DNA amount. Previous studies suggested that DNA polymerases without bypass activity could not perform processive DNA synthesis beyond abasic sites in vitro and our results showed a lack of bypass activity for Phusion, Pfu and KAPA DNA polymerases in this study. Based on this feature, we developed a novel linear amplification method, termed Linear Aamplification for double-stranded DNA using primers with abasic sites near 3' end (abLAFD), to limit the replication error. The amplification efficiency was evaluated by qPCR analysis with a result of approximately a 130-fold increase in target DNA. In a LT-DNA analysis, the abLAFD method can be employed as a pre-PCR. Similar to nested PCRs, primer sets used for the abLAFD method were designed as external primers suitable for commercial multiplex STR amplification assays. The practical performance of the abLAFD method was evaluated by coupling it to a routine PP21 STR analysis using 50 pg and 25 pg DNA. Compared to reference profiles, all abLAFD profiles showed significantly recovered alleles, increased average peak height and heterozygote balance with a comparable stutter ratio. Altogether, our results support the theory that the abLAFD method is a promising strategy coupled to STR typing for forensic LT-DNA analysis.


Assuntos
DNA , Alelos , DNA/análise , DNA/genética , Heterozigoto , Reação em Cadeia da Polimerase/métodos
8.
Am J Hum Genet ; 109(8): 1472-1483, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35931051

RESUMO

Dyskeratosis congenita (DC) is an inherited bone-marrow-failure disorder characterized by a triad of mucocutaneous features that include abnormal skin pigmentation, nail dystrophy, and oral leucoplakia. Despite the identification of several genetic variants that cause DC, a significant proportion of probands remain without a molecular diagnosis. In a cohort of eight independent DC-affected families, we have identified a remarkable series of heterozygous germline variants in the gene encoding thymidylate synthase (TYMS). Although the inheritance appeared to be autosomal recessive, one parent in each family had a wild-type TYMS coding sequence. Targeted genomic sequencing identified a specific haplotype and rare variants in the naturally occurring TYMS antisense regulator ENOSF1 (enolase super family 1) inherited from the other parent. Lymphoblastoid cells from affected probands have severe TYMS deficiency, altered cellular deoxyribonucleotide triphosphate pools, and hypersensitivity to the TYMS-specific inhibitor 5-fluorouracil. These defects in the nucleotide metabolism pathway resulted in genotoxic stress, defective transcription, and abnormal telomere maintenance. Gene-rescue studies in cells from affected probands revealed that post-transcriptional epistatic silencing of TYMS is occurring via elevated ENOSF1. These cell and molecular abnormalities generated by the combination of germline digenic variants at the TYMS-ENOSF1 locus represent a unique pathogenetic pathway for DC causation in these affected individuals, whereas the parents who are carriers of either of these variants in a singular fashion remain unaffected.


Assuntos
Disceratose Congênita , Timidilato Sintase , Disceratose Congênita/genética , Células Germinativas , Heterozigoto , Humanos , Nucleotídeos , Timidilato Sintase/deficiência , Timidilato Sintase/genética
9.
Invest Ophthalmol Vis Sci ; 63(9): 8, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35930268

RESUMO

Purpose: Genetic variants in the complement factor H gene (CFH) have been consistently implicated in age-related macular degeneration (AMD) risk. However, their functional effects are not fully characterized. We previously identified a rare, AMD-associated variant in CFH (P503A, rs570523689) in 19 Amish individuals, but its functional consequences were not investigated. Methods: We performed genotyping for CFH P503A in 1326 Amish individuals to identify additional risk allele carriers. We examined differences for age at AMD diagnosis between carriers and noncarriers. In blood samples from risk allele carriers and noncarriers, we quantified (i) CFH RNA expression, (ii) CFH protein expression, and (iii) C-reactive protein (CRP) expression. Potential changes to the CFH protein structure were interrogated computationally with Phyre2 and Chimera software programs. Results: We identified 39 additional carriers from Amish communities in Ohio and Indiana. On average, carriers were younger than noncarriers at AMD diagnosis, but this difference was not significant. CFH transcript and protein levels in blood samples from Amish carriers and noncarriers were also not significantly different. CRP levels were also comparable in plasma samples from carriers and noncarriers. Computational protein modeling showed slight changes in the CFH protein conformation that were predicted to alter interactions between the CFH 503 residue and other neighboring residues. Conclusions: In total, we have identified 58 risk allele carriers for CFH P503A in the Ohio and Indiana Amish. Although we did not detect significant differences in age at AMD diagnosis or expression levels of CFH in blood samples from carriers and noncarriers, we observed modest structural changes to the CFH protein through in silico modeling. Based on our functional and computational observations, we hypothesize that CFH P503A may affect CFH binding or function rather than expression, which would require additional research to confirm.


Assuntos
Fator H do Complemento , Degeneração Macular , Alelos , Amish/genética , Fator H do Complemento/genética , Fator H do Complemento/metabolismo , Genótipo , Heterozigoto , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/genética , Degeneração Macular/metabolismo , Polimorfismo de Nucleotídeo Único
10.
Stem Cell Res ; 63: 102878, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35917600

RESUMO

E192K missense mutation of TPM1 has been found in different types of cardiomyopathies (e.g., hypertrophic cardiomyopathy, dilated cardiomyopathy, and left ventricular non-compaction), leading to systolic dysfunction, diastolic dysfunction, and/or tachyarrhythmias. Here, we generated a heterozygous TPM1-E192K knock-in human induced pluripotent stem cell (iPSC) line using CRISPR/Cas9-based genome editing system. The cells exhibit normal karyotype, typical stem cell morphology, expression of pluripotency markers and differentiation ability into three germ layers. Accordingly, this cell line could provide a useful cell resource for exploring the pathogenic role of TPM1-E192K mutation in different types of cardiomyopathies.


Assuntos
Cardiomiopatias , Células-Tronco Pluripotentes Induzidas , Sistemas CRISPR-Cas/genética , Cardiomiopatias/metabolismo , Edição de Genes , Heterozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação , Tropomiosina/genética
11.
Hemoglobin ; 46(1): 62-65, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35950578

RESUMO

The population of Viet Nam, is 96.2 million, of which 13.8% are carriers of thalassemia genes. Thalassemia/hemoglobinopathies carriers exist at different frequencies in all 54 ethnic groups of the country. Gene carrier rate and globin gene mutation rate varies ethnically and topographically. The ethnic groups in the Northern Highland region have high rates of α0- and ß0-thalassemia (α0- and ß0-thal), while those in the Southern Middle region have high rates of α+-thalassemia (α+-thal) and Hb E (or codon 26) (HBB: c.79G>A). The lowest is found in La Hu (0.23%), while the highest is found in Raglai (88.6%). Thalassemia prevention and control programs were introduced using prenatal and neonatal diagnosis for the prevention of new thalassemic births. Most existing thalassemia patients are undergoing supportive treatment with regular blood transfusions and iron chelation. Curative treatment by hematopoietic stem cell transplantation is available but is limited to a minority of the patients.


Assuntos
Hemoglobinopatias , Talassemia alfa , Talassemia beta , Feminino , Genótipo , Hemoglobinopatias/genética , Heterozigoto , Humanos , Recém-Nascido , Mutação , Gravidez , Vietnã/epidemiologia , Talassemia alfa/diagnóstico , Talassemia alfa/epidemiologia , Talassemia alfa/genética , Talassemia beta/diagnóstico , Talassemia beta/epidemiologia , Talassemia beta/genética
12.
Hemoglobin ; 46(1): 58-61, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35950579

RESUMO

Thalassemia is a major public health and economical burden in Lao People's Democratic Republic (Lao PDR). This study is aiming to elaborate the current situation of Thalassemia in Laos. α- and ß-thalassemia (α- and ß-thal) includes the common Hb S (HBB: c.20A>T) and hemoglobins (Hbs) such as Hb Constant Spring (Hb CS or HBA2: c.427T>C) and Hb E (HBB: c.79G>A) that are prevalent in the country. Overall, the prevalence of α-thal in Lao PDR is 26.8%. There was high prevalence of homozygous (12.8%) and heterozygous (39.7%) Hb E among migrant workers from Lao PDR who crossed the border to work in Thailand. Iron chelation, blood transfusion, prenatal screening and diagnosis, comprehensive treatment are still the major problems. Splenectomy is still performed. A national registry has still not been established. This is a national economic burden for the country. Thalassemia prevention and control strategy should be established and advocated by the government in order to reduce morbidity and premature mortality.


Assuntos
Talassemia , Talassemia beta , Feminino , Heterozigoto , Humanos , Laos/epidemiologia , Gravidez , Diagnóstico Pré-Natal , Talassemia/epidemiologia , Talassemia/terapia , Talassemia beta/epidemiologia , Talassemia beta/genética , Talassemia beta/terapia
13.
Hemoglobin ; 46(1): 12-14, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35950582

RESUMO

The estimated population of Pakistan is approximately 225,633,392 (225 million). The healthcare delivery system of Pakistan is complex because it includes healthcare subsystems operated by both the federal government and the provincial government. In Pakistan ß-thalassemia (ß-thal) trait frequency ranges between 5.0-7.0%, thus, there are more than 10 million carriers in the country; and every year, around 5000 children are diagnosed to carry ß-thal major (ß-TM) in Pakistan. No standard management protocols exist and blood transfusion remains the mainstay of management. Most of the population belong to the lower socioeconomic strata, family units are large and therefore cannot afford to pay for treatment and management of their thalassemic child. Currently in Pakistan, at the national level, not a single thalassemia prevention program is available to counter this disease. However, at the provincial level some initiatives have been taken, legislation has been approved for premarital screening in Sindh, Khyber Pakhtunkhwa (KPK) and Baluchistan, but implementation remains the issue.


Assuntos
Talassemia , Talassemia beta , Criança , Heterozigoto , Humanos , Programas de Rastreamento , Paquistão/epidemiologia , Talassemia/diagnóstico , Talassemia/epidemiologia , Talassemia/terapia , Talassemia beta/diagnóstico , Talassemia beta/epidemiologia , Talassemia beta/genética
14.
Hemoglobin ; 46(1): 20-26, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35950587

RESUMO

Management and control of hemoglobinopathies are a challenge in India where 67.0% of people reside in rural regions. The GDP spent on health is one of the lowest (1.3%) resulting in high out-of-pocket expenses. The ß-thalassemias are prevalent with an estimated 7500-12000 new births each year. Hb S (HBB: c.20A>T) and Hb E (HBB: c.79G>A) are also common regionally. Over 80 ß-thalassemia (ß-thal) mutations have been characterized in Indians. The δ gene mutations are increasingly being described and their coinheritance in ß-thal carriers leads to a reduction in Hb A2 levels and a misdiagnosis of carriers. Around 15-20 centers offer prenatal diagnosis (PND) mainly in urban regions. The projected annual cost of care of ß-thal patients over a decade (2016-2026) will increase from INR30,000 (US$448) million to INR55,000 (US$820) million if all patients are adequately treated. Cost comparisons are difficult to make with other international studies as the standard of care, cost of medicines and other services vary in different countries. Several centers provide hematopoietic stem cell transplants (HSCTs) for thalassemias, however, only around 250 HSCTs are done annually. Although the cost is high, financial assistance is available for a few patients. There are disparities in the quality of care and to address this a National Policy has been proposed for the management and prevention of hemoglobinopathies that will embark on a comprehensive program, providing adequate care and augmenting the existing public health care services. It will also include training, genetic counseling and easier access to preventive options and a National Registry.


Assuntos
Hemoglobinopatias , Talassemia , Talassemia beta , Feminino , Hemoglobinopatias/diagnóstico , Hemoglobinopatias/epidemiologia , Hemoglobinopatias/genética , Heterozigoto , Humanos , Índia/epidemiologia , Mutação , Gravidez , Talassemia/diagnóstico , Talassemia/epidemiologia , Talassemia/genética , Talassemia beta/diagnóstico , Talassemia beta/epidemiologia , Talassemia beta/genética
15.
Hemoglobin ; 46(1): 15-19, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35950589

RESUMO

Acknowledging and understanding the extent of thalassemia and hemoglobinopathy issues in a country is crucial for the benefit of implementing a national preventive and control program to reduce its prevalence. In order to obtain reliable prevalence data, the gene frequencies of the thalassemias and other hemoglobinopathies should be investigated. Molecular studies on thalassemia have yet to be done for Brunei's population. It was estimated that carriers of thalassemia or hemoglobinopathies in Brunei is approximately 5.0% or less of the overall population. There are about 200 current cases of thalassemia and other hemoglobinopathies including adults and children reported across all four districts of Brunei. Blood parameter analysis, microscopy, hemoglobin (Hb) electrophoresis and high performance liquid chromatography (HPLC) are the most common methods of investigation in aiding diagnosis in the hospital laboratory. Genotyping analysis conducted in an overseas laboratory has been employed to confirm some diagnosis. Compiled data from 2009-2017 at the Hematology Laboratory of the Raja Isteri Pengiran Anak Saleha Hospital, Jalan Putera Al-Muhtadee Billah, Bandar Seri Begawan, Brunei Darussalam, showed that the most reported diagnoses are α-thalassemia (α-thal) trait, ß-thalassemia (ß-thal) trait, heterozygous Hb E (HBB: c.79G>A)/ß-thal, ß-thal major (ß-TM) and ß-thal intermedia (ß-TI). The data reported indicate the importance of establishing a thalassemia registry with relevant data on patients and patient outcomes as a tool for monitoring and improving patient care.


Assuntos
Hemoglobinopatias , Talassemia alfa , Talassemia beta , Adulto , Brunei , Criança , Hemoglobinopatias/genética , Heterozigoto , Humanos , Talassemia alfa/diagnóstico , Talassemia alfa/epidemiologia , Talassemia alfa/genética , Talassemia beta/genética
16.
Int J Mol Sci ; 23(15)2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35955663

RESUMO

Polyploidy is common in cancer cells and has implications for tumor progression and resistance to therapies, but it is unclear whether it is an adaptation of the tumor or the non-adaptive effect of genomic instability. I discuss the possibility that polyploidy reduces the deleterious effects of loss of heterozygosity, which arises as a consequence of mitotic recombination, and which in diploid cells leads instead to the rapid loss of complementation of recessive deleterious mutations. I use computational predictions of loss of heterozygosity to show that a population of diploid cells dividing by mitosis with recombination can be easily invaded by mutant polyploid cells or cells that divide by endomitosis, which reduces loss of complementation, or by mutant cells that occasionally fuse, which restores heterozygosity. A similar selective advantage of polyploidy has been shown for the evolution of different types of asexual reproduction in nature. This provides an adaptive explanation for cyclical ploidy, mitotic slippage and cell fusion in cancer cells.


Assuntos
Neoplasias , Poliploidia , Heterozigoto , Humanos , Perda de Heterozigosidade , Mitose/genética , Neoplasias/genética , Reprodução Assexuada/genética
17.
Mol Neurodegener ; 17(1): 52, 2022 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-35978378

RESUMO

BACKGROUND: Genetic mutations in beta-glucocerebrosidase (GBA) represent the major genetic risk factor for Parkinson's disease (PD). GBA participates in both the endo-lysosomal pathway and the immune response, two important mechanisms involved in the pathogenesis of PD. However, modifiers of GBA penetrance have not yet been fully elucidated. METHODS: We characterized the transcriptomic profiles of circulating monocytes in a population of patients with PD and healthy controls (CTRL) with and without GBA variants (n = 23 PD/GBA, 13 CTRL/GBA, 56 PD, 66 CTRL) and whole blood (n = 616 PD, 362 CTRL, 127 PD/GBA, 165 CTRL/GBA). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Ultrastructural characterization of isolated CD14+ monocytes in the four groups was also performed through electron microscopy. RESULTS: We observed hundreds of differentially expressed genes and dysregulated pathways when comparing manifesting and non-manifesting GBA mutation carriers. Specifically, when compared to idiopathic PD, PD/GBA showed dysregulation in genes involved in alpha-synuclein degradation, aging and amyloid processing. Gene-based outlier analysis confirmed the involvement of lysosomal, membrane trafficking, and mitochondrial processing in manifesting compared to non-manifesting GBA-carriers, as also observed at the ultrastructural levels. Transcriptomic results were only partially replicated in an independent cohort of whole blood samples, suggesting cell-type specific changes. CONCLUSIONS: Overall, our transcriptomic analysis of primary monocytes identified gene targets and biological processes that can help in understanding the pathogenic mechanisms associated with GBA mutations in the context of PD.


Assuntos
Glucosilceramidase , Doença de Parkinson , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Heterozigoto , Humanos , Monócitos/metabolismo , Mutação/genética , Doença de Parkinson/metabolismo , Transcriptoma
18.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 30(4): 1182-1187, 2022 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-35981381

RESUMO

OBJECTIVE: To investigate the molecular epidemiological characteristics of common δß-thalassemia/hereditary persistence of fetal hemoglobin(HPFH) in the prepregnant population in Huadu, and to provide a laboratory basis for prevention and control of thalassemia. METHODS: Blood samples of childbearing age people in Huadu District of Guangzhou who participated in free thalassemia testing from January 2016 to July 2021 were collected for hematological parameters analysis and hemoglobin electrophoresis. Chinese Gγ+(Aγδß)0-thalassemia, SEA-HPFH and Taiwanese deletion ß-thalassemia were detected by Gap-PCR in the samples with higher HbF(≥5%). Primers were designed for the proximal HBG1 and HBG2 promoter, and the point mutations in the proximal promoter region were detected by Sanger sequencing. Hematology parameters data were statistically analyzed. RESULTS: Among 27 088 samples, Thirteen cases of Chinese Gγ+(Aγδß)0-thalassemia and thirty-three cases of SEA-HPFH were detected, which including 3 cases of Chinese Gγ+(Aγδß)0/ßN compounded with --SEA/αα and three cases of SEA-HPFH/ßN compounded with --SEA/αα. 6 carriers with Aγ-196 C>T were also detected; No Taiwanese thalassemia genetype was detected. The total detection rate of common δß-thalassemia/HPFH was 0.19% (52/27 088). There were significant differences in the levels of MCV, MCH, HbA2, and HbF among Chinese Gγ+(Aγδß)0-thalassemia, SEA-HPFH, Aγ-196 C>T (P<0.001). The hematological parameters of Aγ-196C>T combined with α0-thalassemia were similar to those of Chinese Gγ+(Aγδß)0-thalassemia carriers, and only HbA2 was significantly lower than that of the latter, which was helpful for clinical identification. CONCLUSION: δß-thalassemia/HPFH should be included in the scope of thalassemia prevention program in the prepregnant population in Huadu District, and hematological parameters can provide some basis for identifying different types of δß-thalassemia/HPFH.


Assuntos
Talassemia , Talassemia beta , Diagnóstico Diferencial , Hemoglobina Fetal/genética , Heterozigoto , Humanos , Talassemia/genética , Talassemia beta/diagnóstico , Talassemia beta/epidemiologia , Talassemia beta/genética
19.
Pediatr Int ; 64(1): e15283, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35972063

RESUMO

Since the first report in 2009, whole exome sequencing has become the most effective and efficient research tool in human genetics. MIRAGE syndrome is a novel single-gene disorder discovered through whole-exome sequencing for pediatric patients with adrenal insufficiency of unknown etiology, and is caused by de novo heterozygous variants in SAMD9. MIRAGE syndrome was initially discovered as a systemic disease affecting multiple systems, including hematopoietic, immune, endocrine, and gastrointestinal systems but later studies revealed a subset of patients with myelodysplastic syndrome as the sole manifestation. In addition, pathogenic variants in SAMD9L, a paralog gene of SAMD9, were reported to cause an inherited disorder of the hematopoietic system and central nervous system, called ataxia-pancytopenia syndrome. This article reviews the history of MIRAGE syndrome from its discovery to the proposal of SAMD9/SAMD9L syndromes, and discusses directions for future research.


Assuntos
Insuficiência Adrenal , Síndromes Mielodisplásicas , Pancitopenia , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/genética , Criança , Heterozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Sequenciamento Completo do Exoma
20.
Proc Natl Acad Sci U S A ; 119(33): e2114734119, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35947615

RESUMO

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10-5 to 10-3. Among them, the missense variant p.Thr62Pro is detected in ∼1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p.Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD.


Assuntos
Insuficiência Renal Crônica , Uromodulina , Heterozigoto , Humanos , Mutação , Insuficiência Renal Crônica/genética , Uromodulina/genética
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