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1.
Sci Rep ; 14(1): 15003, 2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951544

RESUMO

While the efficacy of GpIIb-IIIa-inhibitors during primary PCI (pPCI) for ST-elevated myocardial infarction (STEMI) has previously been demonstrated, its ongoing role and safety in combination with newer P2Y12-inhibitors is unclear. We therefore sought to compare outcomes between two centers with divergent approaches to the use of GpIIbIIIa antagonists in pPCI. We performed a retrospective chart review of all-comer STEMI patients treated with pPCI at two high-volume Montreal academic tertiary care centers. One center tended to use GpIIb-IIIa-inhibitors up-front in a large proportion of patients (liberal strategy) and the other preferring a bail-out approach (conservative strategy). Baseline patient characteristics and procedural data were compared between the two groups. The main efficacy outcome was rate of no-reflow/slow-reflow and the main safety outcome was BARC ≥ 2 bleeding events. A total of 459 patients were included, of whom 167 (36.5%) were exposed to a GpIIb-IIIa-antagonist. There was a significant overall difference in use of GpIIb-IIIa-antagonist between the two centers (60.5% vs. 16.1%, p < 0.01). Rate of no-reflow/slow-reflow was similar between groups (2.6% vs. 1.4%, p = 0.22). In-hospital rates of unplanned revascularization, stroke and death were also not different between groups. Use of a liberal GpIIb--IIIa-antagonist strategy was however associated with a higher risk of bleeding (OR 3.16, 95% CI 1.57-6.37, p < 0.01), which persisted after adjustment for covariables (adjusted OR 2.85, 95% CI 1.40-5.81, p < 0.01). In this contemporary retrospective cohort, a conservative, bail-out only GpIIb--IIIa-antagonist strategy was associated with a lower incidence of clinically relevant bleeding without any signal for an increase in no-reflow/slow-reflow or ischemic clinical events.


Assuntos
Intervenção Coronária Percutânea , Inibidores da Agregação Plaquetária , Complexo Glicoproteico GPIIb-IIIa de Plaquetas , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Masculino , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Feminino , Pessoa de Meia-Idade , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Idoso , Estudos Retrospectivos , Intervenção Coronária Percutânea/métodos , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Resultado do Tratamento , Hemorragia
2.
NPJ Genom Med ; 9(1): 12, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38374194

RESUMO

Next-generation sequencing (NGS) has been proven to be one of the most powerful diagnostic tools for rare Mendelian disorders. Several studies on the clinical application of NGS in unselected cohorts of Middle Eastern patients have reported a high diagnostic yield of up to 48%, correlated with a high level of consanguinity in these populations. We evaluated the diagnostic utility of NGS-based testing across different clinical indications in 1436 patients from Iran, representing the first study of its kind in this highly consanguineous population. A total of 1075 exome sequencing and 361 targeted gene panel sequencing were performed over 8 years at a single clinical genetics laboratory, with the majority of cases tested as proband-only (91.6%). The overall diagnostic rate was 46.7%, ranging from 24% in patients with an abnormality of prenatal development to over 67% in patients with an abnormality of the skin. We identified 660 pathogenic or likely pathogenic variants, including 241 novel variants, associated with over 342 known genetic conditions. The highly consanguineous nature of this cohort led to the diagnosis of autosomal recessive disorders in the majority of patients (79.1%) and allowed us to determine the shared carrier status of couples for suspected recessive phenotypes in their deceased child(ren) when direct testing was not possible. We also highlight the observations of recessive inheritance of genes previously associated only with dominant disorders and provide an expanded genotype-phenotype spectrum for multiple less-characterized genes. We present the largest mutational spectrum of known Mendelian disease, including possible founder variants, throughout the Iranian population, which can serve as a unique resource for clinical genomic studies locally and beyond.

3.
Int J Neurosci ; : 1-6, 2023 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-37712628

RESUMO

Mutations in ERLIN2 and MFN2 lead to the development of spastic paraplegia-18 (SPG18) and Charcot-Marie-Tooth type-2A (CMT2A), respectively. These disorders are unified by the fact that both can be termed inherited axonopathies. With whole-exome sequencing (WES), more patients of neurological disorders with clinical overlaps receive a genetic result than ever before. This study describes an Iranian family who harbor mutations in ERLIN2 and MFN2, simultaneously. The proband was a 73-year old man who has experienced weakness and spasticity of lower limbs since late childhood. He was diagnosed with hereditary spastic paraplegia (HSP). His WES identified a novel homozygous variant in ERLIN2 as well as a known heterozygous variant in MFN2. These variants were cosegregated with the phenotypes among the family members. His sister with a similar phenotype just carried the homozygous ERLIN2 variant, whereas, his asymptomatic brother and daughter carried the heterozygous variant of MFN2. Re-evaluation of the MFN2 variant carriers by nerve conduction study revealed that only the proband's daughter has peripheral neuropathy. Herein, using WES two distinct disease-causing variants with different modes of inheritance in ERLIN2 and MFN2 were detected in the proband. As expected, individuals with a defined MFN2 variant, p.Arg468His, were asymptomatic or had a mild phenotype. The co-occurrence of such diseases, SPG18 and CMT2A, may result in the milder phenotype to be overlooked or its features considered as a part of the symptoms of other disease. Certainly, providing genetic counseling in such cases can be challenging. These cases reveal the importance of WES.

4.
Clin Genet ; 100(1): 59-78, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33713422

RESUMO

Hearing loss (HL) is one of the most common sensory defects affecting more than 466 million individuals worldwide. It is clinically and genetically heterogeneous with over 120 genes causing non-syndromic HL identified to date. Here, we performed exome sequencing (ES) on a cohort of Iranian families with no disease-causing variants in known deafness-associated genes after screening with a targeted gene panel. We identified likely causal variants in 20 out of 71 families screened. Fifteen families segregated variants in known deafness-associated genes. Eight families segregated variants in novel candidate genes for HL: DBH, TOP3A, COX18, USP31, TCF19, SCP2, TENM1, and CARMIL1. In the three of these families, intrafamilial locus heterogeneity was observed with variants in both known and novel candidate genes. In aggregate, we were able to identify the underlying genetic cause of HL in nearly 30% of our study cohort using ES. This study corroborates the observation that high-throughput DNA sequencing in populations with high rates of consanguineous marriages represents a more appropriate strategy to elucidate the genetic etiology of heterogeneous conditions such as HL.


Assuntos
Exoma/genética , Predisposição Genética para Doença/genética , Perda Auditiva/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Sequenciamento do Exoma/métodos , Adulto Jovem
5.
Clin Genet ; 99(1): 187-192, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32895917

RESUMO

Mutations in adaptor protein complex-4 (AP-4) genes have first been identified in 2009, causing a phenotype termed as AP-4 deficiency syndrome. Since then several patients with overlapping phenotypes, comprised of intellectual disability (ID) and spastic tetraplegia have been reported. To delineate the genotype-phenotype correlation of the AP-4 deficiency syndrome, we add the data from 30 affected individuals from 12 out of 640 Iranian families with ID in whom we detected disease-causing variants in AP-4 complex subunits, using next-generation sequencing. Furthermore, by comparing genotype-phenotype findings of those affected individuals with previously reported patients, we further refine the genotype-phenotype correlation in this syndrome. The most frequent reported clinical findings in the 101 cases consist of ID and/or global developmental delay (97%), speech disorders (92.1%), inability to walk (90.1%), spasticity (77.2%), and microcephaly (75.2%). Spastic tetraplegia has been reported in 72.3% of the investigated patients. The major brain imaging findings are abnormal corpus callosum morphology (63.4%) followed by ventriculomegaly (44.5%). Our result might suggest the AP-4 deficiency syndrome as a major differential diagnostic for unknown hereditary neurodegenerative disorders.


Assuntos
Complexo 4 de Proteínas Adaptadoras/genética , Estudos de Associação Genética , Deficiência Intelectual/genética , Quadriplegia/genética , Complexo 4 de Proteínas Adaptadoras/deficiência , Adolescente , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Pré-Escolar , Estudos de Coortes , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Feminino , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Irã (Geográfico)/epidemiologia , Masculino , Mutação/genética , Linhagem , Fenótipo , Quadriplegia/diagnóstico por imagem , Quadriplegia/patologia
7.
J Hum Genet ; 65(7): 609-617, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32231217

RESUMO

Mutations in the CDC14A (Cell Division-Cycle 14A) gene, which encodes a conserved dual-specificity protein tyrosine phosphatase, have been identified as a cause of autosomal recessive non-syndromic hearing loss (DFNB32) and hearing impairment infertility male syndrome (HIIMS). We used next-generation sequencing to screen six deaf probands from six families segregating sensorineural moderate-to-profound hearing loss. Data analysis and variant prioritization were completed using a custom bioinformatics pipeline. We identified three homozygous loss of function variants (p.Arg345Ter, p.Arg376Ter, and p.Ala451Thrfs*43) in the CDC14A gene, segregating with deafness in each family. Of the six families, four segregated the p.Arg376Ter mutation, one family segregated the p.Arg345Ter mutation and one family segregated a novel frameshift (p.Ala451Thrfs*43) mutation. In-depth phenotyping of affected individuals ruled out secondary syndromic findings. This study implicates the p.Arg376Ter mutation might be as a founder mutation in the Iranian population. It also provides the first semen analysis for deaf males carrying mutations in exon 11 of CDC14A and reveals a genotype-phenotype correlation that delineates between DFNB32 and HIIMS. The clinical results from affected males suggest the NM_033313.2 transcript alone is sufficient for proper male fertility, but not for proper auditory function. We conclude that DFNB32 is a distinct phenotypic entity in males.


Assuntos
Perda Auditiva Neurossensorial/genética , Perda Auditiva/genética , Infertilidade Masculina/genética , Proteínas Tirosina Fosfatases/genética , Adolescente , Adulto , Diagnóstico Diferencial , Éxons/genética , Feminino , Mutação da Fase de Leitura/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Perda Auditiva/complicações , Perda Auditiva/diagnóstico , Perda Auditiva/patologia , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Infertilidade Masculina/complicações , Infertilidade Masculina/diagnóstico , Infertilidade Masculina/patologia , Irã (Geográfico) , Masculino , Linhagem , Adulto Jovem
8.
Iran J Public Health ; 48(10): 1910-1915, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31850270

RESUMO

BACKGROUND: Diagnosis of hereditary hearing loss (HHL) as a heterogeneous disorder is very important especially in countries with high rates of consanguinity where the autosomal recessive pattern of inheritance is prevalent. Techniques such as next-generation sequencing, a comprehensive genetic test using targeted genomic enrichment and massively parallel sequencing (TGE + MPS), have made the diagnosis more cost-effective. The aim of this study was to determine HHL variants with comprehensive genetic testing in our country. METHODS: Fifty GJB2 negative individuals with HHL were referred to the Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, one of the reference diagnostic genetic laboratories in Iran, during a 3-year period between 2014 and 2017. They were screened with the OtoSCOPE test, the targeted genomic enrichment and massively parallel sequencing (TGE + MPS) platform after a detailed history had been taken along with clinical evaluation. RESULTS: Among 32 out of 50 GJB2 negative patients (64%), 34 known pathogenic and novel variants were detected of which 16 (47%) were novel, identified in 10 genes of which the most prevalent were CDH23, MYO7A and MYO15A. CONCLUSION: These results provide a foundation from which to make appropriate recommendations for the use of comprehensive genetic testing in the evaluation of Iranian patients with hereditary hearing loss.

9.
Cell J ; 21(3): 337-349, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31210441

RESUMO

OBJECTIVE: Major birth defects are inborn structural or functional anomalies with long-term disability and adverse impacts on individuals, families, health-care systems, and societies. Approximately 20% of birth defects are due to chromosomal and genetic conditions. Inspired by the fact that neonatal deaths are caused by birth defects in about 20 and 10% of cases in Iran and worldwide respectively, we conducted the present study to unravel the role of chromosome abnormalities, including microdeletion/microduplication(s), in multiple congenital abnormalities in a number of Iranian patients. MATERIALS AND METHODS: In this descriptive cross-sectional study, 50 sporadic patients with Multiple Congenital Anomalies (MCA) were selected. The techniques employed included conventional karyotyping, fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and array comparative genomic hybridisation (array-CGH), according to the clinical diagnosis for each patient. RESULTS: Chromosomal abnormalities and microdeletion/microduplication(s) were observed in eight out of fifty patients (16%). The abnormalities proved to result from the imbalances in chromosomes 1, 3, 12, and 18 in four of the patients. However, the other four patients were diagnosed to suffer from the known microdeletions of 22q11.21, 16p13.3, 5q35.3, and 7q11.23. CONCLUSION: In the present study, we report a patient with 46,XY, der(18)[12]/46,XY, der(18), +mar[8] dn presented with MCA associated with hypogammaglobulinemia. Given the patient's seemingly rare and highly complex chromosomal abnormality and the lack of any concise mechanism presented in the literature to justify the case, we hereby propose a novel mechanism for the formation of both derivative and ring chromosome 18. In addition, we introduce a new 12q abnormality and a novel association of an Xp22.33 duplication with 1q43q44 deletion syndrome. The phenotype analysis of the patients with chromosome abnormality would be beneficial for further phenotype-genotype correlation studies.

10.
Clin Genet ; 95(6): 718-725, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30950035

RESUMO

Neurodevelopmental delay and intellectual disability (ID) can arise from numerous genetic defects. To date, variants in the EXOSC gene family have been associated with such disorders. Using next-generation sequencing (NGS), known and novel variants in this gene family causing autosomal recessive ID (ARID) have been identified in five Iranian families. By collecting clinical information on these families and comparing their phenotypes with previously reported patients, we further describe the clinical variability of ARID resulting from alterations in the EXOSC gene family, and emphasize the role of RNA processing dysregulation in ARID.


Assuntos
Complexo Multienzimático de Ribonucleases do Exossomo/genética , Genes Recessivos , Deficiência Intelectual/genética , Criança , Pré-Escolar , Estudos de Coortes , Consanguinidade , Família , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Irã (Geográfico) , Masculino , Mutação , Linhagem , Sequenciamento do Exoma
11.
Ophthalmic Genet ; 40(2): 141-145, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31006324

RESUMO

BACKGROUND: Cone-rod dystrophies are a group of genetically and phenotypically heterogeneous inherited degenerative retinal diseases primarily affecting macular and cone system function. MFSD8 loss-of-function variants are mainly related to the variant late-infantile neuronal ceroid lipofuscinoses which present with progressive motor and mental regression in combination with seizures, ataxia, and visual impairment. MATERIAL AND METHODS: Clinical examination and genomic DNA extraction were collected from two unrelated Iranian families presenting with autosomal recessive cone-rod dystrophy. The candidate disease-causing variant was screened with whole-exome sequencing and bioinformatics analyses. Sanger sequencing was used for validation and co-segregation analysis. RESULTS: Two previously reported variants (c.1361T>C; p.M454T and c.1235C>T; p.P412L) and in a compound heterozygous pattern in one family and a homozygous variant (c.1361T>C; p.M454T) identical to one of the variants in the first family in MFSD8 gene were identified. Both confirmed by Sanger sequencing and co-segregated with disease status. CONCLUSIONS: Here and for the first time, we reported on two previously variant late-infantile neuronal ceroid lipofuscinoses-associated variants in MFSD8 but in association with a form of cone-rod dystrophy known as non-syndromic macular dystrophy with central cone involvement. Our results support this concept that variant late-infantile neuronal ceroid lipofuscinoses and non-syndromic macular dystrophy with central cone involvement are not different disease entities, but rather allelic diseases and phenotypic variants of the same mutation. Consideration of the milder MFSD8 phenotypes is important against the potentially severe consequences of life-threatening conditions associated with MFSD8 mutations in order to prevent the danger of misdiagnosis as well as the accuracy of genetic counseling.


Assuntos
Distrofias de Cones e Bastonetes/genética , Proteínas de Membrana Transportadoras/genética , Mutação de Sentido Incorreto , Adulto , Distrofias de Cones e Bastonetes/fisiopatologia , Consanguinidade , Feminino , Angiofluoresceinografia , Heterogeneidade Genética , Humanos , Irã (Geográfico) , Masculino , Lipofuscinoses Ceroides Neuronais/genética , Linhagem , Fenótipo , Tomografia de Coerência Óptica , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia , Campos Visuais , Sequenciamento do Exoma
12.
Mol Psychiatry ; 24(7): 1027-1039, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-29302074

RESUMO

Autosomal recessive (AR) gene defects are the leading genetic cause of intellectual disability (ID) in countries with frequent parental consanguinity, which account for about 1/7th of the world population. Yet, compared to autosomal dominant de novo mutations, which are the predominant cause of ID in Western countries, the identification of AR-ID genes has lagged behind. Here, we report on whole exome and whole genome sequencing in 404 consanguineous predominantly Iranian families with two or more affected offspring. In 219 of these, we found likely causative variants, involving 77 known and 77 novel AR-ID (candidate) genes, 21 X-linked genes, as well as 9 genes previously implicated in diseases other than ID. This study, the largest of its kind published to date, illustrates that high-throughput DNA sequencing in consanguineous families is a superior strategy for elucidating the thousands of hitherto unknown gene defects underlying AR-ID, and it sheds light on their prevalence.


Assuntos
Genes Recessivos/genética , Deficiência Intelectual/genética , Adulto , Consanguinidade , Exoma/genética , Família , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Homozigoto , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Mapas de Interação de Proteínas/genética , Sequenciamento do Exoma/métodos , Sequenciamento Completo do Genoma/métodos
13.
Clin Genet ; 95(1): 151-159, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30315573

RESUMO

In outbred Western populations, most individuals with intellectual disability (ID) are sporadic cases, dominant de novo mutations (DNM) are frequent, and autosomal recessive ID (ARID) is very rare. Because of the high rate of parental consanguinity, which raises the risk for ARID and other recessive disorders, the prevalence of ID is significantly higher in near- and middle-east countries. Indeed, homozygosity mapping and sequencing in consanguineous families have already identified a plethora of ARID genes, but because of the design of these studies, DNMs could not be systematically assessed, and the proportion of cases that are potentially preventable by avoiding consanguineous marriages or through carrier testing is hitherto unknown. This prompted us to perform whole-exome sequencing in 100 sporadic ID patients from Iran and their healthy consanguineous parents. In 61 patients, we identified apparently causative changes in known ID genes. Of these, 44 were homozygous recessive and 17 dominant DNMs. Assuming that the DNM rate is stable, these results suggest that parental consanguinity raises the ID risk about 3.6-fold, and about 4.1 to 4.25-fold for children of first-cousin unions. These results do not rhyme with recent opinions that consanguinity-related health risks are generally small and have been "overstated" in the past.


Assuntos
Genes Recessivos , Endogamia , Deficiência Intelectual/genética , Consanguinidade , Exoma/genética , Família , Feminino , Homozigoto , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/patologia , Irã (Geográfico)/epidemiologia , Masculino , Oriente Médio/epidemiologia , Mutação , Linhagem , Sequenciamento do Exoma
14.
Neurol Genet ; 3(3): e148, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28589176

RESUMO

OBJECTIVE: We aimed to generate a review and description of the phenotypic and genotypic spectra of ARHGEF9 mutations. METHODS: Patients with mutations or chromosomal disruptions affecting ARHGEF9 were identified through our clinics and review of the literature. Detailed medical history and examination findings were obtained via a standardized questionnaire, or if this was not possible by reviewing the published phenotypic features. RESULTS: A total of 18 patients (including 5 females) were identified. Six had de novo, 5 had maternally inherited mutations, and 7 had chromosomal disruptions. All females had strongly skewed X-inactivation in favor of the abnormal X-chromosome. Symptoms presented in early childhood with delayed motor development alone or in combination with seizures. Intellectual disability was severe in most and moderate in patients with milder mutations. Males with severe intellectual disability had severe, often intractable, epilepsy and exhibited a particular facial dysmorphism. Patients with mutations in exon 9 affecting the protein's PH domain did not develop epilepsy. CONCLUSIONS: ARHGEF9 encodes a crucial neuronal synaptic protein; loss of function of which results in severe intellectual disability, epilepsy, and a particular facial dysmorphism. Loss of only the protein's PH domain function is associated with the absence of epilepsy.

15.
Hum Mutat ; 38(6): 621-636, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28236339

RESUMO

Intellectual disability (ID) is the hallmark of an extremely heterogeneous group of disorders that comprises a wide variety of syndromic and non-syndromic phenotypes. Here, we report on mutations in two aminoacyl-tRNA synthetases that are associated with ID in two unrelated Iranian families. In the first family, we identified a homozygous missense mutation (c.514G>A, p.Asp172Asn) in the cytoplasmic seryl-tRNA synthetase (SARS) gene. The mutation affects the enzymatic core domain of the protein and impairs its enzymatic activity, probably leading to reduced cytoplasmic tRNASer concentrations. The mutant protein was predicted to be unstable, which could be substantiated by investigating ectopic mutant SARS in transfected HEK293T cells. In the second family, we found a compound heterozygous genotype of the mitochondrial tryptophanyl-tRNA synthetase (WARS2) gene, comprising a nonsense mutation (c.325delA, p.Ser109Alafs*15), which very likely entails nonsense-mediated mRNA decay and a missense mutation (c.37T>G, p.Trp13Gly). The latter affects the mitochondrial localization signal of WARS2, causing protein mislocalization. Including AIMP1, which we have recently implicated in the etiology of ID, three genes with a role in tRNA-aminoacylation are now associated with this condition. We therefore suggest that the functional integrity of tRNAs in general is an important factor in the development and maintenance of human cognitive functions.


Assuntos
Aminoacil-tRNA Sintetases/genética , Deficiência Intelectual/genética , Degradação do RNAm Mediada por Códon sem Sentido/genética , Adolescente , Adulto , Criança , Citocinas/genética , Feminino , Células HEK293 , Homozigoto , Humanos , Deficiência Intelectual/patologia , Irã (Geográfico) , Masculino , Mutação de Sentido Incorreto/genética , Proteínas de Neoplasias/genética , Linhagem , Proteínas de Ligação a RNA/genética
16.
Am J Hum Genet ; 100(2): 216-227, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28065471

RESUMO

Defects of the V-type proton (H+) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of cutis laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic cutis laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.


Assuntos
Cútis Laxa/genética , Mutação de Sentido Incorreto , ATPases Vacuolares Próton-Translocadoras/genética , Adolescente , Alelos , Sequência de Aminoácidos , Estudos de Casos e Controles , Criança , Feminino , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Glicosilação , Complexo de Golgi/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Conformação Proteica , Transporte Proteico , Espectrometria de Massas em Tandem
17.
Am J Med Genet A ; 161A(8): 1915-22, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23825041

RESUMO

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a disorder of the catabolism of the neurotransmitter gamma-aminobutyric acid (GABA) with a very variable clinical phenotype ranging from mild intellectual disability to severe neurological defects. We report here on a large Iranian family with four affected patients presenting with severe intellectual disability, developmental delay and generalized tonic-clonic seizures. Molecular genetic analysis revealed a missense mutation c.901A>G (p.K301E, RefSeq number NM_001080) in ALDH5A1 co-segregating with the disease in the family. The missense mutation affects an amino acid residue that is highly conserved across the animal kingdom. Protein modeling showed that p.K301E most likely leads to a loss of NAD(+) binding and a predicted decrease in the free energy by 6.67 kcal/mol furthermore suggests a severe destabilization of the protein. In line with these in silico observations, no SSADH enzyme activity could be detected in patient lymphoblasts.


Assuntos
1-Pirrolina-5-Carboxilato Desidrogenase/genética , Erros Inatos do Metabolismo dos Aminoácidos/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Adulto , DNA/análise , DNA/genética , Deficiências do Desenvolvimento , Humanos , Irã (Geográfico) , Masculino , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Succinato-Semialdeído Desidrogenase/sangue , Succinato-Semialdeído Desidrogenase/deficiência , Succinato-Semialdeído Desidrogenase/genética , Adulto Jovem
18.
Int J Pediatr Otorhinolaryngol ; 76(8): 1164-74, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22695344

RESUMO

OBJECTIVE: Mutations in GJB2, encoding connexin 26 (CX26), are causally related to autosomal recessive form of non-syndromic hearing loss (NSHL) at the DFNB1 locus and autosomal dominant NSHL at the DFNA3 locus. In this study, we investigated the prevalence of GJB2 mutations in the Iranian deaf population. METHODS: A total of 2322 deaf probands presenting the ethnically diverse Iranian population were screened for variants in GJB2. All persons were first screened for the c.35delG mutation, as this variant is the most prevalent GJB2-deafness causing mutation in the Iranian population. In all persons carrying zero or one c.35delG allele, exons 1 and 2 were then sequenced. RESULTS: In total, 374 (~16%) families segregated GJB2-related deafness caused by 45 different mutations and 5 novel variants. The c.35delG mutation was most commonly identified and accounts for ~65% of the GJB2 mutations found in population studied. CONCLUSION: Our data also show that there is a gradual decrease in the frequency of the c.35delG mutation and of GJB2-related deafness in general in a cline across Iran extending from the northwest to southeast.


Assuntos
Conexinas/genética , Perda Auditiva/genética , Mutação , Conexina 26 , Consanguinidade , Análise Mutacional de DNA , Perda Auditiva/epidemiologia , Humanos , Irã (Geográfico)/epidemiologia , Polimorfismo Genético , Prevalência
19.
Nature ; 478(7367): 57-63, 2011 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-21937992

RESUMO

Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function.


Assuntos
Transtornos Cognitivos/genética , Genes Recessivos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Deficiência Intelectual/genética , Encéfalo/metabolismo , Encéfalo/fisiologia , Ciclo Celular , Consanguinidade , Análise Mutacional de DNA , Éxons/genética , Redes Reguladoras de Genes , Genes Essenciais/genética , Homozigoto , Humanos , Redes e Vias Metabólicas , Mutação/genética , Especificidade de Órgãos , Sinapses/metabolismo
20.
Hum Genet ; 129(2): 141-8, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21063731

RESUMO

Mental retardation (MR) has a worldwide prevalence of around 2% and is a frequent cause of severe disability. Significant excess of MR in the progeny of consanguineous matings as well as functional considerations suggest that autosomal recessive forms of MR (ARMR) must be relatively common. To shed more light on the causes of autosomal recessive MR (ARMR), we have set out in 2003 to perform systematic clinical studies and autozygosity mapping in large consanguineous Iranian families with non-syndromic ARMR (NS-ARMR). As previously reported (Najmabadi et al. in Hum Genet 121:43-48, 2007), this led us to the identification of 12 novel ARMR loci, 8 of which had a significant LOD score (OMIM: MRT5-12). In the meantime, we and others have found causative gene defects in two of these intervals. Moreover, as reported here, tripling the size of our cohort has enabled us to identify 27 additional unrelated families with NS-ARMR and single-linkage intervals; 14 of these define novel loci for non-syndromic ARMR. Altogether, 13 out of 39 single linkage intervals observed in our cohort were found to cluster at 6 different loci on chromosomes, i.e., 1p34, 4q27, 5p15, 9q34, 11p11-q13 and 19q13, respectively. Five of these clusters consist of two significantly overlapping linkage intervals, and on chr 1p34, three single linkage intervals coincide, including the previously described MRT12 locus. The probability for this distribution to be due to chance is only 1.14 × 10(-5), as shown by Monte Carlo simulation. Thus, in contrast to our previous conclusions, these novel data indicate that common molecular causes of NS-ARMR do exist, and in the Iranian population, the most frequent ones may well account for several percent of the patients. These findings will be instrumental in the identification of the underlying genes.


Assuntos
Deficiência Intelectual/genética , Mutação , Transtornos Cromossômicos , Família , Genes Recessivos , Irã (Geográfico) , Método de Monte Carlo
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