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1.
Am J Hum Genet ; 109(5): 967-972, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35523147

RESUMO

The common loss-of-function mutation R577X in the structural muscle protein ACTN3 emerged as a potential target of positive selection from early studies and has been the focus of insightful physiological work suggesting a significant impact on muscle metabolism. Adaptation to cold climates has been proposed as a key adaptive mechanism explaining its global allele frequency patterns. Here, we re-examine this hypothesis analyzing modern (n = 3,626) and ancient (n = 1,651) genomic data by using allele-frequency as well as haplotype homozygosity-based methods. The presented results are more consistent with genetic drift rather than selection in cold climates as the main driver of the ACTN3 R577X frequency distribution in human populations across the world. This Matters Arising paper is in response to Wyckelsma et al. (2021),1 published in The American Journal of Human Genetics. See also the response by Wyckelsma et al. (2022),2 published in this issue.


Assuntos
Actinina , Músculo Esquelético , Actinina/genética , Temperatura Baixa , Frequência do Gene , Homozigoto , Humanos , Músculo Esquelético/metabolismo , Termogênese
2.
Int J Mol Sci ; 23(8)2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35457110

RESUMO

Biallelic gene defects in MFSD8 are not only a cause of the late-infantile form of neuronal ceroid lipofuscinosis, but also of rare isolated retinal degeneration. We report clinical and genetic data of seven patients compound heterozygous or homozygous for variants in MFSD8, issued from a French cohort with inherited retinal degeneration, and two additional patients retrieved from a Swiss cohort. Next-generation sequencing of large panels combined with whole-genome sequencing allowed for the identification of twelve variants from which seven were novel. Among them were one deep intronic variant c.998+1669A>G, one large deletion encompassing exon 9 and 10, and a silent change c.750A>G. Transcript analysis performed on patients' lymphoblastoid cell lines revealed the creation of a donor splice site by c.998+1669A>G, resulting in a 140 bp pseudoexon insertion in intron 10. Variant c.750A>G produced exon 8 skipping. In silico and in cellulo studies of these variants allowed us to assign the pathogenic effect, and showed that the combination of at least one severe variant with a moderate one leads to isolated retinal dystrophy, whereas the combination in trans of two severe variants is responsible for early onset severe retinal dystrophy in the context of late-infantile neuronal ceroid lipofuscinosis.


Assuntos
Lipofuscinoses Ceroides Neuronais , Distrofias Retinianas , Éxons/genética , Homozigoto , Humanos , Proteínas de Membrana Transportadoras/genética , Mutação , Lipofuscinoses Ceroides Neuronais/genética , Distrofias Retinianas/genética
3.
J Pediatr Hematol Oncol ; 44(4): e833-e843, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35398861

RESUMO

This study aimed to report 4 siblings with CD27 deficiency presented with Hodgkin lymphoma. The father of the family, his 2 wives, and 17 children born from these wives were included into the study. CD27 mutation of all the family members with, and without Hodgkin lymphoma were studied. The variants detected by the exome sequencing analysis were verified by Sanger sequencing and analyzed using SeqScape Software 3. It was determined that both the father of the family and his 2 wives carried the same variant heterozygously. Of the children born to the first mother, 2 children were normal, 3 were heterozygous and 5 were homozygous. Four of these 5 homozygous children were diagnosed with Hodgkin lymphoma. Of the children born to the second mother, 1 child was normal, 3 children were heterozygous and 2 children were homozygous, and none of them had developed a malignant event. We also showed that CD27 deficiency may enhance Treg differentiation. According to our information, this study augmented the relationship of Hodgkin lymphoma and CD27 deficiency. The detection of homozygous CD27 variant in all siblings who developed lymphoma strengthened the place of this mutation in the etiology of Hodgkin lymphoma. In contrast, the presence of homozygous siblings with no malignant event suggested the possible contributions of environmental factors on the etiology.


Assuntos
Doença de Hodgkin , Criança , Heterozigoto , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/genética , Homozigoto , Humanos , Mutação , Linhagem
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(4): 442-446, 2022 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-35446985

RESUMO

Congenital thrombotic thrombocytopenic purpura, also known as Upshaw-Schulman syndrome, is a rare autosomal recessive genetic disorder. The main pathogenesis is homozygous or compound heterozygous variants of von Willebrand factor lyase (ADAMTS13) gene mapped to chromosome 9q34, which may result in severe lack of ADAMTS13 which cleaves von Willebrand factor (vWF) multimers in the plasma and increase the risk of microvascular thrombosis, leading to various complications. The advance of research on the pathogenesis of cTTP, recombinant human ADAMTS13 and gene therapy have made breakthroughs which may lead to cure of cTTP. This article has provided a review for the latest progress made in the diagnosis and treatment of cTTP.


Assuntos
Púrpura Trombocitopênica Trombótica , Proteínas ADAM/genética , Proteína ADAMTS13/genética , Homozigoto , Humanos , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/genética , Púrpura Trombocitopênica Trombótica/terapia , Fator de von Willebrand/genética
5.
BMJ Case Rep ; 15(4)2022 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-35387795

RESUMO

Hyperimmunoglobulinaemia D syndrome (HIDS) is a rare autosomal recessive disorder caused by mutations in the mevalonate kinase (MVK) gene, located on chromosome 12. The most common mutation identified in MVK gene so far is V377I. Compound heterozygotes that include this variant may exhibit a more severe phenotype of the disease and homozygotes are rarely found in clinical practice probably they express a milder phenotype. HIDS is a chronic autoinflammatory disease characterised by recurrent febrile episodes, associated with lymphadenopathies, abdominal pain, rash and arthritis. These flares can be triggered by vaccination, minor trauma, surgery and stress.We report a case of a 2-year-old girl who had recurrent attacks of fever associated with cervical lymphadenopathy, macular erythematous skin rash, abdominal pain and aphthous ulcers in the mouth. The patient was found to excrete elevated amounts of urinary mevalonic acid and a homozygous V337I mutation in the MVK gene was identified.


Assuntos
Imunoglobulina D , Deficiência de Mevalonato Quinase , Dor Abdominal , Pré-Escolar , Feminino , Febre , Homozigoto , Humanos , Deficiência de Mevalonato Quinase/diagnóstico , Deficiência de Mevalonato Quinase/genética , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/genética
6.
Atherosclerosis ; 348: 75-81, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35361489

RESUMO

BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (HoFH) is characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels leading to extremely premature atherosclerotic cardiovascular disease. Therefore, healthcare professionals consider HoFH to have major impact on patients' life. Remarkably, little is known on how patients deal with their condition. The aim of this study is to investigate how Dutch patients experience and cope with HoFH in daily life. METHODS: Adult patients with genetically confirmed HoFH, treated at the 3 specialized HoFH-centers in the Netherlands, were interviewed in-depth. Interview transcripts were analyzed according to grounded theory. Health-related quality of life (QoL) and coping were measured with the EuroQol (EQ)-5D-5L questionnaire and the Threatening Medical Situations Inventory (TMSI), respectively. RESULTS: 20 Dutch HoFH patients were interviewed: 50% women, median age 38 years, 60% with cardiovascular disease, 10% on apheresis. Coding of the transcripts resulted in a conceptual model, with disease perception as the central theme. Individual TMSI-results corresponded to the interviews, with most patients showing both monitoring (information-seeking behavior) and blunting (distractive strategies) coping styles. The median EQ-5D-5L health utility score (0.839) was only 5% below the Dutch population (0.887). Transient anxiety was reported when confronted with the consequences of HoFH in daily life. Patients reported high confidence in treatment by a dedicated HoFH center, which helped them cope with their disease. CONCLUSIONS: Dutch HoFH patients use a variety of effective coping mechanisms in such a way that their subjective QoL is only slightly affected. Healthcare professionals can use this knowledge to tailor their care to the specific needs of these patients.


Assuntos
Doenças Cardiovasculares , Hiperlipoproteinemia Tipo II , Adaptação Psicológica , Adulto , Feminino , Homozigoto , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/terapia , Masculino , Qualidade de Vida
7.
BMJ Case Rep ; 15(4)2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35450873

RESUMO

We report a case of a young girl of South Asian descent presented with faltering growth, hepatomegaly, hypertriglyceridaemia and raised transaminases. Subsequent ultrasound scans identified fatty infiltration in her liver, and a liver biopsy showed fibrosis and steatosis. The patient's serum triglycerides normalised without intervention by the age of 28 months. At age 6, whole-exome sequencing of the patient's genome identified novel homozygous variants in the glycerol-3-phosphate dehydrogenase 1 (GPD1) gene, GPD1 c.500G>A (p.Gly167Asp), leading to a diagnosis of GPD1 deficiency.


Assuntos
Hipertrigliceridemia , Hepatopatia Gordurosa não Alcoólica , Criança , Pré-Escolar , Feminino , Hepatomegalia/etiologia , Hepatomegalia/patologia , Homozigoto , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/genética , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética
8.
Genes (Basel) ; 13(4)2022 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-35456440

RESUMO

Microcephaly primary hereditary (MCPH) is a congenital disease characterized by nonsyndromic reduction in brain size due to impaired neurogenesis, often associated with a variable degree of intellectual disability (ID). The genetic etiology of MCPH is heterogeneous and comprises more than 20 loci, nearly all following a recessive inheritance pattern. The first causative gene identified, MCPH1 or Microcephalin, encodes a centrosomal protein that modulates chromosome condensation and cell cycle progression. It is also involved in DNA damage response and telomere maintenance in the nucleus. Despite numerous studies on MCPH1 function, MCPH1-affected individuals are rare and the available clinical reports are not sufficient to define the natural history of the disease. Here, we present a novel patient with congenital microcephaly, ID, language delay, short stature, and other minor features such as strabismus. magnetic resonance imaging revealed ventriculomegaly, simplified gyral pattern in the frontal lobes, and a neuronal migration defect. Genetic testing detected a homozygous deletion of exons 1-8 of MCPH1. We compare the patients' characteristics with a list of features from MCPH1 cases described in the literature, in an effort to provide additional clues for a comprehensive definition of disease presentation and evolution.


Assuntos
Deficiência Intelectual , Microcefalia , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Homozigoto , Humanos , Deficiência Intelectual/genética , Microcefalia/genética , Microcefalia/patologia , Deleção de Sequência
9.
J Exp Med ; 219(6)2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35442418

RESUMO

Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-ß). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses.


Assuntos
Receptor de Interferon alfa e beta , Viroses , Alelos , Criança , Homozigoto , Humanos , Polinésia
10.
Proc Natl Acad Sci U S A ; 119(18): e2200128119, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35482923

RESUMO

SignificanceMessenger RNA (mRNA) splicing is fundamental to protein expression in mammals. Homozygous deletion of single protein components of the splicing machinery or its regulatory factors is embryonic lethal. However, through forward genetic screening in mice, we identified a viable hypomorphic missense mutation of the splicing regulator RNPS1. Homozygous mutant mice displayed altered immune cell development due to excessive tumor necrosis factor (TNF)-dependent immune cell apoptosis. Splicing was impaired in CD8+ T cells and hematopoietic stem cells from RNPS1 mutant mice. TNF knockout rescued hematopoiesis and dramatically reduced splicing defects in RNPS1 hematopoietic cells, demonstrating a surprising link between elevated TNF and defects in splicing caused by RNPS1 deficiency.


Assuntos
Linfócitos T CD8-Positivos , Ribonucleoproteínas , Animais , Linfócitos T CD8-Positivos/metabolismo , Hematopoese/genética , Homozigoto , Mamíferos/metabolismo , Camundongos , Receptores do Fator de Necrose Tumoral/metabolismo , Ribonucleoproteínas/metabolismo , Deleção de Sequência , Fatores de Necrose Tumoral/metabolismo
11.
Stem Cell Res ; 61: 102785, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35421847

RESUMO

Assessment of the electrophysiological properties of cardiomyocytes is necessary for phenotyping cardiac disorders and for drug screening. Optical action potential imaging using a genetically encoded voltage-sensing fluorescent protein (VSFP) allows for high-throughput functional characterization of cardiomyocytes, which offers an advantage over the traditional patch-clamp technique. Here, we knocked VSFP into the AAVS1 safe harbor locus of human iPSCs, generating two stable voltage indicator lines - one heterozygous (MRIi003-A-5) and the other homozygous (MRI003-A-6). Both lines can be used for optical membrane potential recordings and provide a powerful platform for a wide range of applications in cardiovascular biomedicine.


Assuntos
Células-Tronco Pluripotentes Induzidas , Sistemas CRISPR-Cas/genética , Edição de Genes/métodos , Homozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo
12.
Stem Cell Res ; 61: 102772, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35405383

RESUMO

Autosomal recessive polycystic kidney disease is a hereditary fibrocystic disease that involves the kidneys and biliary tract. Its major histological presentations are the fusiform dilatation of renal collecting ducts and the malformation of the hepatobiliary ductal plate. We isolated peripheral blood mononuclear cells from a 21-year-old adult female patient carrying a homozygous p.L2665P mutation in the PKHD1 gene and used nonintegrated exogenous in vitro differentiation vectors for reprogramming to obtain human induced pluripotent stem cells. The induced pluripotent stem cells thus established had a normal karyotype, expressed markers of pluripotency, and could differentiate into three germ layers in the body.


Assuntos
Células-Tronco Pluripotentes Induzidas , Rim Policístico Autossômico Recessivo , Adulto , Feminino , Homozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Leucócitos Mononucleares , Masculino , Mutação/genética , Rim Policístico Autossômico Recessivo/genética , Rim Policístico Autossômico Recessivo/patologia , Adulto Jovem
13.
Acta Neuropathol Commun ; 10(1): 56, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35440040

RESUMO

Chordoid meningioma is a morphological variant of meningioma designated as WHO grade 2. However, the recurrence rates varied widely in different case series, and to date, a unifying molecular genetic signature has not been identified. Among 1897 meningiomas resected at our institution, we identified 12 primary chordoid meningiomas from 12 patients. Histologically, all 12 cases had predominant (> 50%) chordoid morphology. Ten were otherwise grade 1, and two were also atypical. We performed DNA global methylation profile, copy number variation analysis, and targeted next-generation sequencing on 11 chordoid meningiomas, and compared to those of 51 non-chordoid, mostly high grade meningiomas. The chordoid meningiomas demonstrated a unique methylation profile in tSNE, UMAP, and hierarchical heatmap clustering analyses of the most differentially methylated CpGs. The most common copy number variation in chordoid meningioma was loss of 1p (7/11, 64%). Three chordoid meningiomas had 2p loss, which was significantly higher than the non-chordoid control cohort (27% vs 7.2%, p = 0.035). 22q loss was only seen in the two cases with additional atypical histological features. Chordoid meningiomas were enriched in mutations in chromatin remodeling genes EP400 (8/11,73%) KMT2C (4/11, 36%) and KMT2D (4/11, 36%), and showed low or absent NF2, TERT, SMO, and AKT1 mutations. Prognosis wise, only one case recurred. This case had atypical histology and high-grade molecular features including truncating NF2 mutation, 1p, 8p, 10, 14, 22q loss, and homozygous deletion of CDKN2A/B. Progression free survival of chordoid, otherwise grade 1 meningioma was comparable to non-chordoid WHO grade 1 meningioma (p = 0.75), and significantly better than chordoid WHO grade 2 meningioma (p = 0.019). Conclusion: the chordoid histology alone may not justify a universal WHO grade 2 designation. Screening for additional atypical histological or molecular genetic features is recommended.


Assuntos
Neoplasias Meníngeas , Meningioma , Variações do Número de Cópias de DNA , Epigênese Genética , Homozigoto , Humanos , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/cirurgia , Meningioma/diagnóstico , Meningioma/genética , Meningioma/cirurgia , Deleção de Sequência
14.
Acta Neuropathol Commun ; 10(1): 42, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35361262

RESUMO

Classification of gliomas involves the combination of histological features with molecular biomarkers to establish an integrated histomolecular diagnosis. Here, we report on the application and validation of a set of molecular assays for glioma diagnostics based on digital PCR technology using the QX200™ Droplet Digital™ PCR (ddPCR) system. The investigated ddPCR-based assays enable the detection of diagnostically relevant glioma-associated mutations in the IDH1, IDH2, H3-3A, BRAF, and PRKCA genes, as well as in the TERT promoter. In addition, ddPCR-based assays assessing diagnostically relevant copy number alterations were studied, including 1p/19q codeletion, gain of chromosome 7 and loss of chromosome 10 (+ 7/-10), EGFR amplification, duplication of the BRAF locus, and CDKN2A homozygous deletion. Results obtained by ddPCR were validated by other methods, including immunohistochemistry, Sanger sequencing, pyrosequencing, microsatellite analyses for loss of heterozygosity, as well as real-time PCR- or microarray-based copy number assays. Particular strengths of the ddPCR approach are (1) its high analytical sensitivity allowing for reliable detection of mutations even with low mutant allele frequencies, (2) its quantitative determination of mutant allele frequencies and copy number changes, and (3) its rapid generation of results within a single day. Thus, in line with other recent studies our findings support ddPCR analysis as a valuable approach for molecular glioma diagnostics in a fast, quantitative and highly sensitive manner.


Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioma/diagnóstico , Glioma/genética , Glioma/patologia , Homozigoto , Humanos , Isocitrato Desidrogenase/genética , Patologia Molecular , Reação em Cadeia da Polimerase em Tempo Real , Deleção de Sequência
15.
BMC Genomics ; 23(1): 252, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35365085

RESUMO

Cystic fibrosis (CF, MIM# 219,700) is an autosomal recessive disease caused by pathogenic variants within the CFTR gene. It was shown that genetic variants located in cis can affect disease severity or treatment response because of additive or epistatic effects. Studies on the prevalence of complex alleles in Russian CF patients have just begun. Aim To evaluate frequencies and genetic background of complex alleles carrying c.1521_1523delCTT (F508del) and c.1399C>T (L467F), c.2562T>G (T854=) or c.4389G>A (Q1463=) in cis; to determine clinical consequences of complex allele c.[1399C>T;1521_1523delCTT] ([L467;F508del]) in Russian CF patients. Methods Sequencing of coding regions of CFTR gene and analysis of polymorphic markers in CF patients carrying F508del variant. Comparing of clinical features in two groups patients having genotypes [L467F;F508del];[F508del] (group 1) and [F508del];[F508del] (group 2). Results Frequency of [L467F;F508del] allele linked to 2-2-21-6-17-13 haplotype was 4.42%, of [F508del;T854=;Q1463=] allele linked to haplotype 1-2-21-6-17-13 - 2.2% in F508del chromosomes. No differences in disease severity in patients carrying complex allele [L467F;F508del] and patients homozygous for F508del was found. Conclusion The frequency of complex alleles associated with F508del was at least 6.6% in Russian CF patients, which should be taken into account for the decision on optimal treatment options with CFTR modulators.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Peptídeos Cíclicos/metabolismo , Alelos , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Haplótipos , Homozigoto , Humanos
16.
BMJ Case Rep ; 15(4)2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35365473

RESUMO

Hypertriglyceridaemia in infancy is usually secondary to underlying metabolic disorder which usually has a genetic basis unlike the adult population. One such recently described entity is transient infantile hypertriglyceridaemia (HTGTI). In this disorder, mutation in glycerol-3-phosphate (G3P) dehydrogenase gene leads to deficiency of G3P dehydrogenase resulting in hypertriglyceridaemia and hepatomegaly. Clinical features tend to improve with age but may develop fibrosis. Our patient presented in infancy with hypoglycaemia, hepatomegaly, high transaminases and hypertriglyceridaemia. Limited genetic test for glycogen storage disorder was negative and was kept under follow-up. On follow-up, he developed hepatic lesion and his hepatomegaly with hypertriglyceridaemia persisted. There are only a few cases reported worldwide and none has reported development of adenoma so far. This could be the first report of development of adenoma in transient HTGTI.


Assuntos
Adenoma de Células Hepáticas , Hipertrigliceridemia , Neoplasias Hepáticas , Adenoma de Células Hepáticas/genética , Adulto , Homozigoto , Humanos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/genética , Neoplasias Hepáticas/genética , Masculino , Mutação
17.
Orphanet J Rare Dis ; 17(1): 149, 2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35379254

RESUMO

BACKGROUND: Homozygous or compound heterozygous variants in the KLHL40 gene cause nemaline myopathy 8 (NEM8), a severe autosomal recessive muscle disorder characterized by prenatal polyhydramnios, fetal akinesia or hypokinesia, joint contractures, fractures, respiratory failure and dysphagia. Currently, 46 individuals with NEM8 have been described in the literature, and 30 variants in KLHL40 have been identified. RESULTS: Here, we reported five individuals from four unrelated Chinese families who presented common features of nemaline myopathy and infrequent clinical characteristics. Whole-exome sequencing (WES) was used to identify the causative gene. WES identified a recurrent missense variant c.1516A>C (p.Thr506Pro) and a novel frameshift variant c.543del (p.Ser182Profs*17) in KLHL40 in patient 1, a nonsense variant c.602G>A (p.Trp201*) and a missense variant c.1516A>C (p.Thr506Pro) in KLHL40 in patient 2, and homozygous variant c.1516A>C (p.Thr506Pro) in KLHL40 in patient 3 and both siblings (patients 4 and 5), all of which were confirmed by Sanger sequencing. Next, we estimated the incidence of this disorder in the southern and northern Chinese population to be 4.59/106 and 2.95/106, respectively, based on the cumulative allele frequency of pathogenic variants in internal database. CONCLUSION: The results of our study expand the mutation spectrum of KLHL40 and enrich our understanding of the clinical characteristics of NEM8. Genetic counseling was provided for the four families involved in this study. Given the severity and the relatively high incidence of this condition, we strongly suggest that KLHL40 be incorporated into a carrier screening panel for the Chinese population.


Assuntos
Miopatias da Nemalina , /genética , China , Feminino , Homozigoto , Humanos , Proteínas Musculares/genética , Mutação , Miopatias da Nemalina/genética , Miopatias da Nemalina/patologia , Gravidez
18.
Sci Rep ; 12(1): 5435, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35361830

RESUMO

Mendelian variants can determine both insemination success and neonatal survival and thus influence fertility and rearing success of cattle. We present 24 deficient homozygous haplotype regions in the Holstein population of Switzerland and provide an overview of the previously identified haplotypes in the global Holstein breed. This study encompasses massive genotyping, whole-genome sequencing (WGS) and phenotype association analyses. We performed haplotype screenings on almost 53 thousand genotyped animals including 114 k SNP data with two different approaches. We revealed significant haplotype associations to several survival, birth and fertility traits. Within haplotype regions, we mined WGS data of hundreds of bovine genomes for candidate causal variants, which were subsequently evaluated by using a custom genotyping array in several thousand breeding animals. With this approach, we confirmed the known deleterious SMC2:p.Phe1135Ser missense variant associated with Holstein haplotype (HH) 3. For two previously reported deficient homozygous haplotypes that show negative associations to female fertility traits, we propose candidate causative loss-of-function variants: the HH13-related KIR2DS1:p.Gln159* nonsense variant and the HH21-related NOTCH3:p.Cys44del deletion. In addition, we propose the RIOX1:p.Ala133_Glu142del deletion as well as the PCDH15:p.Leu867Val missense variant to explain the unexpected low number of homozygous haplotype carriers for HH25 and HH35, respectively. In conclusion, we demonstrate that with mining massive SNP data in combination with WGS data, we can map several haplotype regions and unravel novel recessive protein-changing variants segregating at frequencies of 1 to 5%. Our findings both confirm previously identified loci and expand the spectrum of undesired alleles impairing reproduction success in Holstein cattle, the world's most important dairy breed.


Assuntos
Fertilidade , Alelos , Animais , Bovinos/genética , Feminino , Fertilidade/genética , Genótipo , Haplótipos , Homozigoto
19.
Reprod Biol Endocrinol ; 20(1): 41, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35232447

RESUMO

BACKGROUND: Multiple morphological abnormalities of the sperm flagella (MMAF) is a subtype of severe asthenoteratozoospermia with poorly understood genetic etiology. SPAG6 is a core axonemal component that plays a critical role in the formation of cilia and sperm flagella. Previous studies have reported that mutations in SPAG6 cause primary ciliary dyskinesia (PCD), but the association between SPAG6 gene variants and the MMAF phenotype has not yet been described. METHODS: We performed whole-exome sequencing (WES) in two unrelated Han Chinese men with MMAF. Sanger sequencing was used to validate the candidate variants. Routine semen analysis was carried out according to the WHO guidelines (5th Edition). Sperm morphology was assessed using modified Papanicolaou staining. Scanning and transmission electron microscopy (S/TEM) was performed to observe the ultrastructural defects of the sperm flagella. Western blot analysis and immunofluorescence (IF) of spermatozoa were performed to examine the expression of SPAG6 protein. Assisted fertilization with intracytoplasmic sperm injection (ICSI) was applied. RESULTS: Two homozygous SPAG6 variants were identified by WES and Sanger validation in two patients with MMAF phenotype (F1 II-1: c.308C > A, p. A103D; F2 II-1: c. 585delA, p. K196Sfs*6). Semen analysis showed progressive rates of less than 1%, and most of the spermatozoa presented MMAF by Papanicolaou staining. TEM revealed that the overall axonemal ultrastructure was disrupted and primarily presented an abnormal "9 + 0" configuration. No other PCD-related symptoms were found on physical examination and medical consultations, as well as lung CT screening. The level of SPAG6 protein was significantly decreased in the spermatozoa, and IF analysis revealed that SPAG6 staining was extremely weak and discontinuous in the sperm flagella of the two patients. Notably, F1 II-1 and his wife conceived successfully after undergoing ICSI. CONCLUSIONS: Our research provides new evidence for a potential correlation between SPAG6 variants and the MMAF phenotype.


Assuntos
Astenozoospermia/genética , Proteínas dos Microtúbulos/genética , Teratozoospermia/genética , Adulto , Astenozoospermia/complicações , Astenozoospermia/patologia , China , Consanguinidade , Análise Mutacional de DNA/métodos , Homozigoto , Humanos , Infertilidade Masculina/etiologia , Infertilidade Masculina/genética , Masculino , Mutação , Linhagem , Fenótipo , Cauda do Espermatozoide/patologia , Cauda do Espermatozoide/ultraestrutura , Espermatozoides/anormalidades , Espermatozoides/ultraestrutura , Teratozoospermia/complicações , Teratozoospermia/patologia , Sequenciamento Completo do Exoma
20.
Anim Genet ; 53(3): 307-316, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35285059

RESUMO

Obesity is associated with increased serum fibrinogen level. Myostatin (MSTN), a strong inhibitor of skeletal muscle growth, is recognized as a potential target for obesity. However, the effect of MSTN inhibition on fibrinogen is not largely known. The objective of the present study was to explore fibrinogen levels after MSTN inhibition. Fibrinogen levels and the fibrin clot structure of MSTN homozygous knockout (KO) and wild-type (WT) pigs (n = 4 in each group) were investigated. The protein expression of fibrinogen in the serum and liver of KO pigs decreased greatly (1.6-fold loss for serum and 2.5-fold loss for liver). KO pigs showed significantly decreased gene expression of fibrinogen chains: FGA (fibrinogen-α; 11-fold), FGB (fibrinogen-ß; 8-fold) and FGG (fibrinogen-γ; 7.4-fold). The basal transcriptional regulators of fibrinogen, HNF1 (hepatocyte nuclear factor 1) and CEBP-α (CCAAT/Enhancing-binding protein-alpha) were remarkably down-regulated after interruption of MSTN expression by siRNA (small interfering RNA) in cultured hepatocytes (about 2- and 4-fold, respectively). Compared with WT pigs, KO pigs displayed altered fibrin clot structure with thinner fibers, decreased turbidity and increased permeability. The findings indicate that the inhibition of MSTN could affect fibrinogen levels and the fibrin clot structure.


Assuntos
Miostatina , Doenças dos Suínos , Animais , Fibrina/genética , Fibrina/metabolismo , Fibrinogênio/genética , Fibrinogênio/metabolismo , Homozigoto , Músculo Esquelético/metabolismo , Miostatina/genética , Obesidade , Suínos/genética
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