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1.
Womens Health (Lond) ; 18: 17455057221122597, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36129002

RESUMO

Here, we reported a case of a 16-year-old Chinese female patient (46, XX) diagnosed as 17α-hydroxylase/17, 20-lyase deficiency (17-OHD) in June 2018 and over 3 years follow-up outcomes; 17-OHD is a rare form of congenital adrenal hyperplasia. The patient presented with primary amenorrhea, underdeveloped secondary sexual characteristics, hypertension and hypokalemia. Hormonal findings revealed decreased estrogen and androgen, increased progesterone, low cortisol concentration and compensatory high adrenocorticotropic hormone level. Mutation analysis of the CYP17A1 gene identified the c.1459_1467del GACTCTTTC homozygous deletion in exon 8, namely, D487_F489del mutation, resulting in the deletion of Aspartate-Serine-Phenylalanine amino acids. The patient's father and mother were all heterozygous carriers of this mutation. The diagnosis and follow-up outcomes provided useful insights to support clinical decision-making and appropriate treatment.


Assuntos
Liases , Esteroide 17-alfa-Hidroxilase , Adolescente , Hormônio Adrenocorticotrópico/genética , Androgênios , Ácido Aspártico/genética , Estrogênios , Feminino , Seguimentos , Homozigoto , Humanos , Hidrocortisona , Liases/genética , Oxigenases de Função Mista/genética , Fenilalanina/genética , Progesterona , Deleção de Sequência , Serina/genética , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo
2.
BMC Genom Data ; 23(1): 73, 2022 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-36131251

RESUMO

BACKGROUND: Describing how genetic history shapes the pattern of medically relevant variants could improve the understanding of how specific loci interact with each other and affect diseases and traits prevalence. The Qatari population is characterized by a complex history of admixture and substructure, and the study of its population genomic features would provide valuable insights into the genetic landscape of functional variants. Here, we analyzed the genomic variation of 186 newly-genotyped healthy individuals from the Qatari peninsula. RESULTS: We discovered an intricate genetic structure using ancestry related analyses. In particular, the presence of three different clusters, Cluster 1, Cluster 2 and Cluster 3 (with Near Eastern, South Asian and African ancestry, respectively), was detected with an additional fourth one (Cluster 4) with East Asian ancestry. These subpopulations show differences in the distribution of runs of homozygosity (ROH) and admixture events in the past, ranging from 40 to 5 generations ago. This complex genetic history led to a peculiar pattern of functional markers under positive selection, differentiated in shared signals and private signals. Interestingly we found several signatures of shared selection on SNPs in the FADS2 gene, hinting at a possible common evolutionary link to dietary intake. Among the private signals, we found enrichment for markers associated with HDL and LDL for Cluster 1(Near Eastern ancestry) and Cluster 3 (South Asian ancestry) and height and blood traits for Cluster 2 (African ancestry). The differences in genetic history among these populations also resulted in the different frequency distribution of putative loss of function variants. For example, homozygous carriers for rs2884737, a variant linked to an anticoagulant drug (warfarin) response, are mainly represented by individuals with predominant Bedouin ancestry (risk allele frequency G at 0.48). CONCLUSIONS: We provided a detailed catalogue of the different ancestral pattern in the Qatari population highlighting differences and similarities in the distribution of selected variants and putative loss of functions. Finally, these results would provide useful guidance for assessing genetic risk factors linked to consanguinity and genetic ancestry.


Assuntos
Genética Populacional , Varfarina , Anticoagulantes , Consanguinidade , Homozigoto , Humanos
3.
Orphanet J Rare Dis ; 17(1): 359, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36109815

RESUMO

OBJECTIVE: Alström syndrome (ALMS) is a rare autosomal recessive genetic disorder that is caused by homozygous or compound heterozygous mutation in the ALMS1 gene. Dilated cardiomyopathy (DCM) is one of the well-recognized features of the syndrome ranging from sudden-onset infantile DCM to adult-onset cardiomyopathy, sometimes of the restrictive hypertrophic form with a poor prognosis. We aimed to evaluate severe cardiomyopathy in Alström syndrome in infancy and display susceptible specific mutations of the disease, which may be linked to severe DCM. Secondarily we reviewed published mutations in ALMS1 with cardiomyopathies in the literature. METHOD: We represent new mutagenic alleles related to severe cardiomyopathy and cardiac outcome in this patient cohort. We evaluated echocardiographic studies of nine Turkish patients diagnosed with Alström syndrome (between 2014 and 2020, at age two weeks to twenty years). Thus, we examined the cardiac manifestations of a single-centre prospective series of nine children with specific ALMS mutations and multisystem involvement. All patients underwent genetic and biochemical testing, electrocardiograms, and echocardiographic imaging to evaluate systolic strain with speckle tracking. RESULTS: Four of the patients died from cardiomyopathy. Three patients (including three of the four fatalities) with the same mutation (c.7911dupC [p.Asn2638Glnfs*24]) had cardiomyopathy with intra-familial variability in the severity of cardiomyopathy. Global longitudinal strain, a measure of systolic contractile function, was abnormal in all patients that can be measured. CONCLUSION: Cardiac function in ALMS patients with infantile cardiomyopathy appears to have different clinical spectrums depending on the mutagenic allele. The c.7911dupC (p. Asn2638Glnfs*24) mutation can be related to severe cardiomyopathy. Parents can be informed and consulted about the progression of severe cardiomyopathy in a child carrying this mutagenic allele.


Assuntos
Síndrome de Alstrom , Cardiomiopatias , Cardiomiopatia Dilatada , Adulto , Síndrome de Alstrom/diagnóstico , Síndrome de Alstrom/genética , Cardiomiopatias/genética , Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/genética , Criança , Homozigoto , Humanos , Mutação/genética
4.
Nat Commun ; 13(1): 5215, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36064805

RESUMO

Hemochromatosis is one of the most common inherited metabolic diseases among white populations and predominantly originates from a homozygous C282Y mutation in the HFE gene. The G > A transition at position c.845 of the gene causes misfolding of the HFE protein, ultimately resulting in its absence at the cell membrane. Consequently, the lack of interaction with the transferrin receptors 1 and 2 leads to systemic iron overload. We screened potential gRNAs in a highly precise cell culture assay and applied an AAV8 split-vector expressing the adenine base editor ABE7.10 and our candidate gRNA in 129-Hfetm.1.1Nca mice. Here we show that a single injection of our therapeutic vector leads to a gene correction rate of >10% and improved iron metabolism in the liver. Our study presents a proof-of-concept for a targeted gene correction therapy for one of the most frequent hereditary diseases affecting humans.


Assuntos
Adenina , Proteína da Hemocromatose , Hemocromatose , Adenina/metabolismo , Animais , Ferritinas/genética , Hemocromatose/genética , Hemocromatose/metabolismo , Hemocromatose/terapia , Proteína da Hemocromatose/genética , Proteína da Hemocromatose/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Homozigoto , Ferro/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Mutação , Transferrina/metabolismo
5.
Sci Rep ; 12(1): 15587, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114266

RESUMO

Primordial germ cells (PGCs), the precursors of sperm and oocytes, pass on the genetic material to the next generation. The previously established culture system of chicken PGCs holds many possibilities for functional genomics studies and the rapid introduction of desired traits. Here, we established a CRISPR/Cas9-mediated genome editing protocol for the genetic modification of PGCs derived from chickens with blue eggshell color. The sequence targeted in the present report is a provirus (EAV-HP) insertion in the 5'-flanking region of the SLCO1B3 gene on chromosome 1 in Araucana chickens, which is supposedly responsible for the blue eggshell color. We designed pairs of guide RNAs (gRNAs) targeting the entire 4.2 kb provirus region. Following transfection of PGCs with the gRNA, genomic DNA was isolated and analyzed by mismatch cleavage assay (T7EI). For absolute quantification of the targeting efficiencies in homozygous blue-allele bearing PGCs a digital PCR was established, which revealed deletion efficiencies of 29% when the wildtype Cas9 was used, and 69% when a high-fidelity Cas9 variant was employed. Subsequent single cell dilutions of edited PGCs yielded 14 cell clones with homozygous deletion of the provirus. A digital PCR assay proved the complete absence of this provirus in cell clones. Thus, we demonstrated the high efficiency of the CRISPR/Cas9 system in introducing a large provirus deletion in chicken PGCs. Our presented workflow is a cost-effective and rapid solution for screening the editing success in transfected PGCs.


Assuntos
Provírus , RNA Guia , Animais , Sistemas CRISPR-Cas/genética , Galinhas/genética , Células Germinativas , Homozigoto , Masculino , Reação em Cadeia da Polimerase , Provírus/genética , RNA Guia/genética , Sêmen , Deleção de Sequência
6.
Zhongguo Dang Dai Er Ke Za Zhi ; 24(9): 1047-1052, 2022.
Artigo em Chinês | MEDLINE | ID: mdl-36111725

RESUMO

A girl, aged 11 years, was admitted due to recurrent rash on the whole body and mucosa for 10 years, and typical rash was erythema at the perioral region, hand-foot joints, vulva, and perianal region, with blisters, erosions, and ulcers on the erythema. The girl was improved after zinc supplementation. Her younger brother had similar rash and medical history. The histopathological examination showed epidermal parakeratosis with mild hyperkeratosis, severe spongiform edema of the stratum corneum, significant proliferation of acanthocytes, and vacuolation of keratinocytes. The genetic testing revealed that both the girl and her younger brother had a homozygous mutation of c.1456(exon9)delG in the SLC39A4 gene, and thus the girl was diagnosed with acrodermatitis enteropathica. It is concluded that for children with recurrent rash on the limbs and at the perioral region, genetic testing should be performed as early as possible to make a confirmed diagnosis, and a sufficient dose of zinc supplementation should be given, while the levels of trace elements such as blood zinc should be regularly monitored.


Assuntos
Acrodermatite , Proteínas de Transporte de Cátions , Exantema , Oligoelementos , Acrodermatite/diagnóstico , Acrodermatite/genética , Acrodermatite/patologia , Proteínas de Transporte de Cátions/genética , Criança , Exantema/etiologia , Feminino , Homozigoto , Humanos , Masculino , Recidiva , Zinco
7.
Orphanet J Rare Dis ; 17(1): 361, 2022 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-36115991

RESUMO

BACKGROUND: Congenital hereditary endothelial dystrophy (CHED) is a rare form of corneal dystrophy caused by SLC4A11 gene variations. This study aims to find the genetic alterations in SLC4A11, in two Indian familial CHED cases with affected members n = 3 and n = 2 respectively and five sporadic CHED cases using direct sequencing, followed by in silico analysis and characterization of the identified variants. RESULTS: All three affected members of the first CHED family were identified with a novel homozygous c.1514C > G (p.Ser489Trp) variation while second family showed presence of a compound heterozygous variation c.529A > C (p.Arg161Arg) + c.2461insT (p.Val805fs). Among five sporadic cases, two showed novel changes, homozygous c.1487G > T (p.Ser480Ile) and c.620-2A > G, while the other one had previously reported homozygous c.2653C > T (p.Arg869Cys) variation. The remaining two cases did not reveal the presence of SLC4A11-related pathogenic variations. The identified variations were excluded from the Indian control (n = 80). In silico analysis using homology-based protein modeling and pathogenicity prediction tools, which revealed these alterations as pathogenic, changing their protein stability, local flexibility, residue contact clashes, and the hydrogen bond interactions. CONCLUSIONS: This study contributed to the CHED mutational spectrum, adding four novel variations and confirming a previously reported one. It demonstrates different type of variations in CHED cases, including coding, non-coding, homozygous, synonymous, and compound heterozygous variations. The identified variations revealed different degrees of pathogenic effects in silico. Moreover, two sporadic cases could not be identified with pathogenic variation emphasizing the involvement of other genes or genetic mechanisms.


Assuntos
Proteínas de Transporte de Ânions , Distrofias Hereditárias da Córnea , Proteínas de Transporte de Ânions/genética , Proteínas de Transporte de Ânions/metabolismo , Antiporters/genética , Antiporters/metabolismo , Distrofias Hereditárias da Córnea/genética , Homozigoto , Humanos , Mutação/genética
8.
Med. clín (Ed. impr.) ; 159(5): 240-247, septiembre 2022. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-JHG-303

RESUMO

El diagnóstico de mesotelioma pleural difuso requiere en la mayoría de los casos una biopsia pleural, realizada bajo control de imagen (ecografía o tomografía computarizada) o mediante toracoscopia. La pérdida de expresión de BAP1 o de MTAP (inmunohistoquímica) y la deleción homocigota de CDKN2A (hibridación fluorescente in situ) constituyen los marcadores moleculares básicos para el diagnóstico de mesotelioma. El tipo histológico y el estado funcional del paciente son los factores pronósticos más importantes. El control del derrame pleural se puede realizar a través de la inserción de catéteres pleurales tunelizados, bien como medida aislada (p. ej. pacientes no susceptibles de terapia multimodal que se han diagnosticado por citología del líquido pleural o biopsia guiada por imagen) o combinada con la administración de talco aerosolizado durante una toracoscopia diagnóstica. La inmunoterapia constituye una de las primeras líneas de tratamiento en pacientes inoperables, particularmente en las variedades histológicas bifásicas o sarcomatosas. (AU)


The diagnosis of diffuse pleural mesothelioma requires in most cases a pleural biopsy, performed either under imaging guidance (ultrasound or computed tomography) or thoracoscopy. Loss of BAP1 or MTAP expression (immunohistochemistry) and homozygous deletion of CDKN2A (fluorescence in situ hybridization) are the basic molecular markers for the diagnosis of mesothelioma. The histologic type and patient's performance status are the most important prognostic factors. Pleural effusion can be managed by the insertion of tunneled pleural catheters, either as a stand-alone measure (e.g., patients not amenable to multimodality therapy who have been diagnosed by pleural fluid cytology or image-guided biopsy) or combined with the administration of aerosolized talc during a diagnostic thoracoscopy. Immunotherapy is one of the front-line approaches in inoperable patients, particularly in biphasic or sarcomatous histologic varieties. (AU)


Assuntos
Humanos , Biomarcadores Tumorais/metabolismo , Homozigoto , Hibridização In Situ , Fluorescência , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/genética , Neoplasias Pleurais/terapia , Mesotelioma/diagnóstico , Mesotelioma/genética , Mesotelioma/terapia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Deleção de Sequência
9.
J Trop Pediatr ; 68(5)2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-36130307

RESUMO

Hemoglobin S is caused by a nucleotide change in HBB gene (HBB:c.20A>T, p.Glu6Val), is presented in diverse forms: simple carriers (HbSA), homozygotes (HbSS) also known as sickle cell anemia, and compound heterozygotes with other ß-hemoglobinopathies. It is worldwide distributed, in Mexico, is frequently observed in the southern states Guerrero, Oaxaca and Chiapas. Elevated fetal hemoglobin (HbF) is associated with mild phenotype; single-nucleotide variants (SNVs) in modifier genes, such as BCL11A, HBG2, HBBP1 pseudogene and HBS1L-MYB intergenic region, upregulate HbF synthesis. The aim of this study was to identify HbF regulating genetic variants in HbSS and HbSA Mexican subjects. We studied 39 individuals (HbSS = 24, 61%, HbSA = 15, 39%) from Chiapas (67%) and Guerrero (33%), peripheral blood was collected in ethylenediamine tetraacetic acid (EDTA) for molecular and hematological studies, DNA was isolated by salting-out technic and genotyping was performed through allelic discrimination by real time polymerase chain reaction (RT-PCR) using Taqman® probes for 15 SNV (in BCL11A: rs6706648, rs7557939, rs4671393, rs11886868, rs766432, rs7599488, rs1427407; HBS1L-MYB: rs28384513, rs7776054, rs9399137, rs4895441, rs9402686, rs1320963; HBG2: rs7482144; and HBBP1: rs10128556). The obtained data were analyzed using IMB SPSS v.22.0 software. All minor alleles were observed in frequencies over 0.05, the most frequent was rs9402686 (0.82), while the less frequent was rs101028556 (0.08). In HbSS group, the mean fetal hemoglobin was 11.9 ± 5.9% and was significantly elevated in BCL11A rs11886868 wildtype homozygotes and in carriers of HBS1L-MYB intergenic region rs7776054 (p = 0.04 and p = 0.03, respectively). In conclusion, in HbSS Mexican patients, two SNVs were observed related to increased HbF; BCL11A rs11886868 and HBS1L-MYB rs7776054.


Sickle cell anemia (SCA) is one of the most common types of hemoglobinopathies in people of African ancestry, it is caused by homozygosity of HbS mutation (HBB:c.20A>T). It is known that fetal hemoglobin plays a key role in decreasing HbS polymerization which damages the erythrocyte structure and is responsible for the characteristic hemolytic crises endured by these patients. Single-nucleotide variant (SNV) in genes that regulate fetal hemoglobin (HbF) after birth have been associated with its increment, thus ameliorating the hematologic phenotype of this pathology and other ß-hemoglobinopathies. Therefore, in this study, we identified, for the first time in Mexican patients with SCA (HbSS) and HbS carriers (HbSA), the presence of 15 SNVs on BCL11A, HBS1L-MYB and HBG2; all HbSS patients had anemia and elevated HbF; 2 variants were related to increased HbF rs11688888C of BCL11A and rs7776054G of HBSIL-MYB; and finally, all minor alleles were found at a frequency higher than 0.05.


Assuntos
Anemia Falciforme , Hemoglobina Fetal , DNA Intergênico , Ácido Edético , Hemoglobina Fetal/genética , Hemoglobina Falciforme/genética , Heterozigoto , Homozigoto , Humanos , México , Nucleotídeos , Polimorfismo de Nucleotídeo Único , Proteínas Repressoras/genética
10.
JCI Insight ; 7(18)2022 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-36134655

RESUMO

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672C>T, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell-derived (iPSC-derived) islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulated genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function through a combination treatment of chemical chaperones mitigated detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increased insulin secretion in SC-islets. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.


Assuntos
Células-Tronco Pluripotentes Induzidas , Atrofia Óptica , Síndrome de Wolfram , Homozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas de Membrana/genética , Atrofia Óptica/genética , Atrofia Óptica/patologia , Síndrome de Wolfram/diagnóstico , Síndrome de Wolfram/genética , Síndrome de Wolfram/patologia
11.
PLoS One ; 17(9): e0274743, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36121861

RESUMO

The objective of this study was to describe the runs of homozygosity (ROH) detected in the Mexican Holstein population and to associate them with milk, fat and protein yields, and conformation final score. After imputation and genomic quality control, 4,227 genotyped animals with 100,806 SNPs markers each were used. ROH with a minimum length of 1 Mb and a minimum of 10 SNPs were included in the analysis. One heterozygous SNP marker and five missing genotypes per ROH were allowed. A total of 425,098 ROH were found in the studied population (71.83 ± 10.73 ROH per animal), with an average length and coverage of 4.80 ± 0.77 Mb, and 276.89 Mb, respectively. The average chromosome length covered by ROH was 10.40 ± 3.70 Mb. ROH between 1 and 2 Mb were the most frequent in the population (51.33%) while those between 14 and 16 Mb were the least frequent (1.20%). Long chromosomes showed a larger number of ROH. Chromosomes 10 and 20, had a greater percentage of their length covered by ROH because they presented a largest number of long ROH (>8 Mb). From the total ROH, 17 were detected in 1,847 animals and distributed among different chromosomes, and were associated with milk, fat and protein yield and percentage, and conformation final score. Of the ROH with effects on production traits, the majority were found with a length between 1 and 4 Mb. These results show evidence of genomic regions preserved by genetic selection and associated with the improvement of the productivity and functionality of dairy cattle.


Assuntos
Genoma , Endogamia , Animais , Bovinos/genética , Genótipo , Homozigoto , Fenótipo
12.
Rev Med Inst Mex Seguro Soc ; 60(5): 577-583, 2022 Aug 31.
Artigo em Espanhol | MEDLINE | ID: mdl-36049072

RESUMO

Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disorder showing peripheral hypotonia, atrophy, and weakness in the extremities and bulbar muscles. It is caused by the homozygous deletion of the SMN1 gene on chromosome 5q13. Before 2016, there was no treatment to modify the disease, and in that year it was approved nusinersen, the first drug available to treat this disease, whose action mechanism consists in regulating the SMN2 gene to increase the survival motor neuron (SMN) levels. More recently, the gene therapy onasemnogene aberparvovec-xioi (OAX) was approved for patients under two years of age. The human SMN1 gene is delivered intravenously through an adeno-associated viral type 9 vector. Both therapies appear to show significant improvement in motor function without the presence of severe adverse effects. However, it is unclear whether both treatments can be used together. Clinical case: A 24-month-old male patient with a diagnosis of SMA at 18 months of age. First, he was treated with intrathecal nusinersen administration and later with OAX. When assessing the CHOP INTEND and HFSME function scales, the patient showed an increase in the performance of his motor functions. Conclusion: OAX and nusinersen could be considered in sequence therapies in the presence of SMA. However, this therapy is not yet well established and has not been studied in the long term.


Introducción: la atrofia muscular espinal (AME) es un trastorno neuromuscular autosómico recesivo que se presenta con hipotonía periférica, atrofia y debilidad en las extremidades y músculos bulbares. Es causada por la deleción en estado homocigoto del gen SMN1 en el cromosoma 5q13. Antes de 2016, no había tratamiento modificador de la enfermedad y en ese año fue aprobado el nusinersen, el primer medicamento disponible para esta enfermedad, cuyo mecanismo de acción es modular el gen SMN2 para producir mayor cantidad de proteína de supervivencia de la motoneurona (SMN). En 2019 se aprobó el onasemnogene abeparvovec-xioi (OAX), primer fármaco disponible que utiliza terapia génica. Este se puede emplear únicamente en pacientes menores de dos años y consiste en administrar vía intravenosa el gen humano SMN1 mediante un vector viral adenoasociado tipo 9, con lo que se inicia la producción de proteína SMN. Ambas terapias han demostrado mejoría significativa de la función motora y sin presencia de eventos adversos serios. Sin embargo, aún no está claramente establecido si ambas terapias pueden usarse en conjunto. Caso clínico: paciente de sexo masculino de 24 meses de edad con diagnóstico de AME a los 18 meses, el cual fue tratado inicialmente con nusinersen intratecal y posteriormente con OAX. Al evaluar las escalas de función CHOP INTEND y HFSME el paciente presentó un aumento en el desempeño de sus funciones motoras. Conclusión: el OAX y el nusinersen podrían considerarse terapias en secuencia ante la AME. Sin embargo, esta terapia aún no está bien establecida y no se ha estudiado a largo plazo.


Assuntos
Atrofia Muscular Espinal , Pré-Escolar , Homozigoto , Humanos , Masculino , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/genética , Deleção de Sequência
13.
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
14.
Turk J Pediatr ; 64(4): 795-803, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36082656

RESUMO

BACKGROUND: Fucosidosis is a rare, autosomal recessive lysosomal storage disease caused by alpha L- fucosidase enzyme deficiency in all tissues. Here, we identify a patient with a novel homozygous pathogenic variant and atypical clinical findings and summarized the clinical and molecular features of Turkish patients reported in the literature and present. CASE: The patient was born to consangineous parents at the 28th week of gestation. He had developmental delay that was attributed to prematurity. At he age of 2.5 years, brain magnetic resonans imaging revealed hyperintensities of symmetrical periventricular, subcortical, centrum semiovale and corona radiata regions on T2 and FLAIR weighted images. He developed seizures and showed developmental regression at he age of 3,5 years. Beside, coarse facial features and hepatomegaly were detected on phsyical examination. Lysosomal enzyme analysis revelaed alfa fucosidase deficiency and molecular genetic analysis identified a novel homozygous pathogenic p. Lys431 fs variant in FUCA1 gene. CONCLUSIONS: In Turkish patients no distinguishable clinical and radiologic finding could be established. Molecular analysis was performed in few patients. Increasing of molecular and biochemical facilities might enable to make diagnosis and increase the prevalence of the disease in countries with high rate of consanguineous marriages. Moreover, it will provide genetic counseling, and enlighten the therapeutic effects of hematopoietic stem cell transplantation.


Assuntos
Fucosidose , Encéfalo/patologia , Pré-Escolar , Fucosidose/diagnóstico , Fucosidose/genética , Fucosidose/terapia , Homozigoto , Humanos , Masculino , alfa-L-Fucosidase/genética
15.
Orphanet J Rare Dis ; 17(1): 331, 2022 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-36056436

RESUMO

BACKGROUND: Galactose epimerase (GALE) deficiency is a rare hereditary disorder of galactose metabolism with only a few cases described in the literature. This study aims to present the data of patients with GALE deficiency from different countries included through the Galactosemia Network to further expand the existing knowledge and review the current diagnostic strategy, treatment and follow-up of this not well characterized entity. METHODS: Observational study collecting medical data from December 2014 to April 2022 of 22 not previously reported patients from 14 centers in 9 countries. Patients were classified as generalized or non-generalized based on their genotype, enzyme activities in different tissues and/or clinical picture and professional judgment of the treating physician. RESULTS: In total 6 patients were classified as generalized and 16 as non-generalized. In the generalized group, acute neonatal illness was reported in 3, cognitive and developmental delays were present in 5 and hearing problems were reported in 3. Four generalized patients were homozygous for the genetic variant NM_001008216.2:c.280G > A (p.Val94Met). In the non-generalized group, no clearly related symptoms were found. Ten novel genetic variants were reported in this study population. CONCLUSION: The phenotypic spectrum of GALE deficiency ranges from asymptomatic to severe. The generalized patients have a phenotype that is in line with the 9 described cases in the literature and prescribing dietary interventions is the cornerstone for treatment. In the non-generalized group, treatment advice is more difficult. To be able to offer proper counseling, in addition to red blood cell enzyme activity, genetic studies, transferrin glycoform analysis and enzymatic measurements in fibroblasts are recommended. Due to lack of facilities, additional enzymatic testing is not common practice in many centers nor a tailored long-term follow-up is performed.


Assuntos
Galactosemias , Galactosemias/genética , Galactosemias/metabolismo , Genótipo , Homozigoto , Humanos , Sistema de Registros , UDPglucose 4-Epimerase/genética , UDPglucose 4-Epimerase/metabolismo
16.
Reprod Health ; 19(1): 190, 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36088419

RESUMO

BACKGROUND: It has been proved that mutations in the PADI6 gene can cause early embryo arrest. This study describes a newly discovered mutation in PADI6 that expands the genetic spectrum of early embryo arrest. METHODS: Peripheral blood of a patient diagnosed with early embryo arrest was collected for whole-exome sequencing. Sanger sequencing was performed to confirm this mutation. The effects of the variant were investigated in human embryonic kidney 293T (HEK293T) cells using western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence. RESULTS: A novel homozygous mutation in PADI6 was identified in the proband. The patient carried a frameshift insertion mutation c.558dupA (p.Thr187Asnfs*48), which was located in the protein arginine deiminase middle domain. The variant destroyed PADI6 protein expression and reduced PADI6 mRNA expression in HEK293T cells. CONCLUSIONS: The newly identified mutation in PADI6 accounts for early embryo arrest. It expands the spectrum of genetic causes and phenotypes of infertility in humans. These findings also provide an additional possible diagnostic marker for patients with recurrent in vitro fertilization/intracytoplasmic sperm injection failure.


Some infertile patients experience multiple in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) failure owing to recurrent early embryo arrest. However, the underlying mechanisms remain largely unknown. Due to the development of whole-exome sequencing, early embryo arrest has been confirmed as a type of Mendelian disease. This study aimed to identify the genetic cause of early embryo arrest in patients and to expand the genetic spectrum. Furthermore, it can help doctors offer better suggestions to such patients and prevent patients from suffering from multiple IVF/ICSI failures.


Assuntos
Sêmen , Células HEK293 , Homozigoto , Humanos , Masculino , Mutação , Proteína-Arginina Desiminase do Tipo 6
17.
Int J Mol Sci ; 23(15)2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35955418

RESUMO

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype-phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c.859G>C-positive modifier variant in SMN2. All were studied by a specific NGS method to allow a deep characterization of the entire SMN region. Analysis of two homozygous cases for the variant allowed us to identify a specific haplotype, Smn2-859C.1, in association with c.859G>C. Two other cases with the c.859G>C variant in their two SMN2 copies showed a second haplotype, Smn2-859C.2, in cis with Smn2-859C.1, assembling a more complex allele. We also identified a previously unreported variant in intron 2a exclusively linked to the Smn2-859C.1 haplotype (c.154-1141G>A), further suggesting that this region has been ancestrally conserved. The deep molecular characterization of SMN2 in our cohort highlights the importance of testing c.859G>C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype-phenotype correlations and improve prognostic outcomes.


Assuntos
Atrofia Muscular Espinal , Estudos de Associação Genética , Homozigoto , Humanos , Íntrons , Atrofia Muscular Espinal/genética , Mutação , Fenótipo , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/genética
18.
Development ; 149(17)2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36017799

RESUMO

Signals from the endothelium play a pivotal role in pancreatic lineage commitment. As such, the fate of the epithelial cells relies heavily on the spatiotemporal recruitment of the endothelial cells to the embryonic pancreas. Although it is known that VEGFA secreted by the epithelium recruits the endothelial cells to the specific domains within the developing pancreas, the mechanism that controls the timing of such recruitment is poorly understood. Here, we have assessed the role of focal adhesion kinase (FAK) in mouse pancreatic development based on our observation that the presence of the enzymatically active form of FAK (pFAK) in the epithelial cells is inversely correlated with vessel recruitment. To study the role of FAK in the pancreas, we conditionally deleted the gene encoding focal adhesion kinase in the developing mouse pancreas. We found that homozygous deletion of Fak (Ptk2) during embryogenesis resulted in ectopic epithelial expression of VEGFA, abnormal endothelial recruitment and a delay in endocrine and acinar cell differentiation. The heterozygous mutants were born with no pancreatic phenotype but displayed gradual acinar atrophy due to cell polarity defects in exocrine cells. Together, our findings imply a role for FAK in controlling the timing of pancreatic lineage commitment and/or differentiation in the embryonic pancreas by preventing endothelial recruitment to the embryonic pancreatic epithelium.


Assuntos
Células Endoteliais , Animais , Diferenciação Celular/genética , Proteína-Tirosina Quinases de Adesão Focal , Homozigoto , Camundongos , Deleção de Sequência
19.
Sci Rep ; 12(1): 14589, 2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-36028527

RESUMO

Recently, whole-exome sequencing (WES) has been used for genetic diagnoses of patients who remain otherwise undiagnosed. WES was performed in 177 Japanese patients with undiagnosed conditions who were referred to the Tokai regional branch of the Initiative on Rare and Undiagnosed Diseases (IRUD) (TOKAI-IRUD). This study included only patients who had not previously received genome-wide testing. Review meetings with specialists in various medical fields were held to evaluate the genetic diagnosis in each case, which was based on the guidelines of the American College of Medical Genetics and Genomics. WES identified diagnostic single-nucleotide variants in 66 patients and copy number variants (CNVs) in 11 patients. Additionally, a patient was diagnosed with Angelman syndrome with a complex clinical phenotype upon detection of a paternally derived uniparental disomy (UPD) [upd(15)pat] wherein the patient carried a homozygous DUOX2 p.E520D variant in the UPD region. Functional analysis confirmed that this DUOX2 variant was a loss-of-function missense substitution and the primary cause of congenital hypothyroidism. A significantly higher proportion of genetic diagnoses was achieved compared to previous reports (44%, 78/177 vs. 24-35%, respectively), probably due to detailed discussions and the higher rate of CNV detection.


Assuntos
Exoma , Doenças não Diagnosticadas , Variações do Número de Cópias de DNA , Oxidases Duais , Homozigoto , Humanos , Doenças Raras , Dissomia Uniparental , Sequenciamento Completo do Exoma
20.
Neurobiol Aging ; 119: 67-76, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35977442

RESUMO

The APOE-ε4 allele is known to predispose to amyloid deposition and consequently is strongly associated with Alzheimer's disease (AD) risk. There is debate as to whether the APOE gene accounts for all genetic variation of the APOE locus. Another question which remains is whether APOE-ε4 carriers have other genetic factors influencing the progression of amyloid positive individuals to AD. We conducted a genome-wide association study in a sample of 5,390 APOE-ε4 homozygous (ε4ε4) individuals (288 cases and 5102 controls) aged 65 or over in the UK Biobank. We found no significant associations of SNPs in the APOE locus with AD in the sample of ε4ε4 individuals. However, we identified a novel genome-wide significant locus associated to AD, mapping to DAB1 (rs112437613, OR = 2.28, CI = 1.73-3.01, p = 5.4 × 10-9). This identification of DAB1 led us to investigate other components of the DAB1-RELN pathway for association. Analysis of the DAB1-RELN pathway indicated that the pathway itself was associated with AD, therefore suggesting an epistatic interaction between the APOE locus and the DAB1-RELN pathway.


Assuntos
Doença de Alzheimer , Apolipoproteína E4 , Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Estudo de Associação Genômica Ampla , Genótipo , Homozigoto , Humanos , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética
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