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1.
N Engl J Med ; 384(25): 2406-2417, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34161705

RESUMO

BACKGROUND: Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related (ATG) genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare. METHODS: We performed a genetic, clinical, and neuroimaging analysis involving five families. Mechanistic investigations were conducted with the use of patient-derived fibroblasts, skeletal muscle-biopsy specimens, mouse embryonic fibroblasts, and yeast. RESULTS: We found deleterious, recessive variants in human ATG7, a core autophagy-related gene encoding a protein that is indispensable to classical degradative autophagy. Twelve patients from five families with distinct ATG7 variants had complex neurodevelopmental disorders with brain, muscle, and endocrine involvement. Patients had abnormalities of the cerebellum and corpus callosum and various degrees of facial dysmorphism. These patients have survived with impaired autophagic flux arising from a diminishment or absence of ATG7 protein. Although autophagic sequestration was markedly reduced, evidence of basal autophagy was readily identified in fibroblasts and skeletal muscle with loss of ATG7. Complementation of different model systems by deleterious ATG7 variants resulted in poor or absent autophagic function as compared with the reintroduction of wild-type ATG7. CONCLUSIONS: We identified several patients with a neurodevelopmental disorder who have survived with a severe loss or complete absence of ATG7, an essential effector enzyme for autophagy without a known functional paralogue. (Funded by the Wellcome Centre for Mitochondrial Research and others.).


Assuntos
Anormalidades Múltiplas/genética , Ataxia/genética , Proteína 7 Relacionada à Autofagia/genética , Autofagia/genética , Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Autofagia/fisiologia , Proteína 7 Relacionada à Autofagia/fisiologia , Células Cultivadas , Cerebelo/anormalidades , Simulação por Computador , Face/anormalidades , Feminino , Fibroblastos , Genes Recessivos , Humanos , Lactente , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Malformações do Sistema Nervoso/genética , Linhagem , Fenótipo
2.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070858

RESUMO

Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases.


Assuntos
Demência Frontotemporal/genética , Genes Dominantes , Genes Recessivos , Ataxias Espinocerebelares/genética , Ubiquitina-Proteína Ligases , Adulto , Idade de Início , Idoso , Família , Feminino , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Expressão Gênica , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Dobramento de Proteína , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/metabolismo , Ataxias Espinocerebelares/patologia
3.
J Pak Med Assoc ; 71(3): 816-821, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34057927

RESUMO

Objective: To explore the genetic cause of autosomal recessive retinitis pigmentosa in consanguineous families. METHODS: The multi-centre study was conducted from July 2015 to June 2018 at Liaquat University of Medical and Health Sciences, Jamshoro, the University of Sindh, Jamshoro, and Islamia University, Bahawalpur, Pakistan, and comprised families affected with non-syndromic autosomal recessive retinitis pigmentosa. Ophthalmological investigations were done to assess the fundus of the patients and the status of the disease. Pedigrees were drawn and family histories were recorded to find out the mode of inheritance. A 10cc sample of whole blood was obtained from each participant and deoxyribonucleic acid was extracted. Homozygosity mapping was performed using three short tandem repeat polymorphisms closely linked to phosphodiesterase 6A gene, and the linked families were Sanger-sequenced for identification of the mutation. Bioinformatic tools were used to design amplification refractory mutation system assay and to assess the protein structure and pathogenic effects of the mutation. RESULTS: In the 80 consanguineous families, there were 464 individuals, and, of them, 236(51%) were affected with their age ranging between 4 and 80 years. Family history and pedigree drawings revealed autosomal recessive retinitis pigmentosa with early childhood onset. Linkage analysis indicated the homozygosity in 6(7.5%) families. Sanger-sequencing revealed a common mutation c.304C>A (p.Arg102Ser); segregating with the disease in the linked families. Conclusion: The findings may offer effective genetic counselling and minimise disease penetration in consanguineous families.


Assuntos
Retinite Pigmentosa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Consanguinidade , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Proteínas do Olho/genética , Genes Recessivos , Humanos , Pessoa de Meia-Idade , Mutação , Paquistão , Retinite Pigmentosa/genética , Adulto Jovem
4.
Am J Hum Genet ; 108(5): 764-785, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33811808

RESUMO

Tandem repeats represent one of the most abundant class of variations in human genomes, which are polymorphic by nature and become highly unstable in a length-dependent manner. The expansion of repeat length across generations is a well-established process that results in human disorders mainly affecting the central nervous system. At least 50 disorders associated with expansion loci have been described to date, with half recognized only in the last ten years, as prior methodological difficulties limited their identification. These limitations still apply to the current widely used molecular diagnostic methods (exome or gene panels) and thus result in missed diagnosis detrimental to affected individuals and their families, especially for disorders that are very rare and/or clinically not recognizable. Most of these disorders have been identified through family-driven approaches and many others likely remain to be identified. The recent development of long-read technologies provides a unique opportunity to systematically investigate the contribution of tandem repeats and repeat expansions to the genetic architecture of human disorders. In this review, we summarize the current and most recent knowledge about the genetics of repeat expansion disorders and the diversity of their pathophysiological mechanisms and outline the perspectives of developing personalized treatments in the future.


Assuntos
Pesquisa Biomédica/tendências , Expansão das Repetições de Trinucleotídeos , Antecipação Genética , Efeito Fundador , Genes Dominantes , Genes Recessivos , Genoma Humano/genética , Humanos , Fatores de Tempo , Expansão das Repetições de Trinucleotídeos/genética
6.
BMC Plant Biol ; 21(1): 182, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863289

RESUMO

BACKGROUND: Trichomes are excellent model systems for the analysis of cell differentiation and play essential roles in plant protection. From cucumber inbred line 'WD1', we identified an EMS-induced trichome abnormally developing mutant, nps, which exhibited smaller, denser and no pyramid-shaped head trichomes. RESULTS: Using F2 and BC1 populations constructed from a cross between nps and '9930', the genetic analysis showed that the nps trait is controlled by a single recessive nuclear gene. We identified CsNps by map-based cloning with 576 individuals of the F2 population generated from the cross of nps and inbred line '9930'. The CsNps was located at a 13.4-kb genomic region on chromosome 3, which region contains three predicted genes. Sequence analysis showed that only one single nucleotide mutation (C → T) between 9930 and nps was found in the second exon of Csa3G748220, a plant-specific class I HD-Zip gene. The result of allelism test also indicated that nps is a novel allelic mutant of Mict (Micro-trichome). Thus, nps was renamed mict-L130F. By comparing the transcriptome of mict-L130F vs WD1 and 06-2 (mict) vs 06-1 (wildtype, near-isogenic line of 06-2), several potential target genes that may be related to trichome development were identified. CONCLUSIONS: Our results demonstrate that Mict-L130F is involved in the morphogenesis of trichomes. Map-based cloning of the Mict-L130F gene could promote the study of trichome development in cucumber.


Assuntos
Cucumis sativus/genética , Genes de Plantas , Proteínas de Plantas/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Tricomas/anatomia & histologia , Cucumis sativus/anatomia & histologia , Genes Recessivos , Proteínas de Plantas/metabolismo , Fatores de Transcrição/metabolismo , Tricomas/genética
7.
Hum Genet ; 140(7): 1011-1029, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33710394

RESUMO

The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case.


Assuntos
Exoma/genética , Deficiência Intelectual/genética , Família , Feminino , Finlândia , Genes Recessivos/genética , Predisposição Genética para Doença/genética , Genótipo , Homozigoto , Humanos , Masculino , Linhagem , Sequenciamento Completo do Exoma/métodos
8.
J Genet ; 1002021.
Artigo em Inglês | MEDLINE | ID: mdl-33707353

RESUMO

India has a large heterogeneous population with its unique social and genetic characteristics. Tradition of marriage between specific caste groups have produced unique characteristics to the mutation spectrum of genetic disorders and may be a higher prevalence of autosomal recessive (AR) disorders in some communities. We observed that in many nonconsanguineous families with rare autosomal disorders, maternally and paternally inherited mutations are same, indicating common ancestor. In this era of genomic techniques, finding homozygous regions have become easy. It was seen that the patients with AR disorders, who were homozygous for the disease causing pathogenic / likely pathogenic variations, have large stretches (0.6-188 Mb) of homozygosity around the causative sequence variations. SNP microarray data of patients from consanguineous and nonconsanguineous families also showed that even patients from nonconsanguineous families had 3-49 Mb size regions of homozygosity. Long stretches of homozygosity around homozygous rare pathogenic variants in nonconsanguineous families with rare AR disorders supports the notion that these couples may have a common ancestor for more than six generations and the system of marriages between same groups. Hence, using the strategy of homozygosity by descent even in nonconsanguineous families can be fruitful in identifying the novel pathogenic variations and novel genes.


Assuntos
Genes Recessivos , Doenças Genéticas Inatas/genética , Homozigoto , Mucopolissacaridose IV/genética , Mutação , Grupo com Ancestrais do Continente Asiático/genética , Consanguinidade , Humanos , Índia
10.
Eur J Endocrinol ; 184(5): K15-K20, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33690157

RESUMO

Introduction: Autosomal recessive forms of pseudohypoaldosteronism are caused by genetic defects in the epithelial sodium channel. Little is known about the long-term outcome and medication needs during childhood and adolescence. Objective: This study reports a single-centre experience of children affected with this ultra-rare condition over a 37-year period. Methods: We report the clinical presentation, growth, neuro-development, associated conditions, mortality and medication dosing and administration for 12 affected children from eight families. Results: All children were presented within the first 2 weeks of life with life-threatening, severe hyperkalaemia and hyponatraemia. All parents were consanguineous and of South Asian, Middle Eastern or African ethnic origin. Eight children had homozygous mutations in the SCNN1A and SCNN1G genes, encoding the epithelial sodium channel subunits alpha and gamma, respectively, including one novel mutation. Three children died (25%) and two (16%) had severe neurological impairment post-cardiac arrest secondary to hyperkalaemia. One affected female had a successful pregnancy at the age of 28 years. Conclusion: Despite high mortality and morbidity in this condition, survival with normal physical and neurological outcome is possible, justifying intensive management to prevent electrolyte imbalance.


Assuntos
Pseudo-Hipoaldosteronismo/diagnóstico , Pseudo-Hipoaldosteronismo/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Consanguinidade , Canais Epiteliais de Sódio/genética , Família , Feminino , Genes Recessivos , Homozigoto , Humanos , Masculino , Mutação , Pseudo-Hipoaldosteronismo/genética , Pseudo-Hipoaldosteronismo/mortalidade , Estudos Retrospectivos , Reino Unido/epidemiologia , Adulto Jovem
11.
Am J Hum Genet ; 108(4): 608-619, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33740458

RESUMO

The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6,447 exome sequences of healthy, genetically unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal-recessive (AR) genes and that 0.8%-1% of European couples are at risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins but is significantly more increased for skeletal disorders and intellectual disabilities due to their distinct genetic architecture.


Assuntos
Consanguinidade , Grupo com Ancestrais do Continente Europeu/genética , Características da Família , Genes Recessivos/genética , Variação Genética/genética , Fenótipo , Estudos de Coortes , Europa (Continente)/etnologia , Exoma/genética , Feminino , Testes Genéticos , Saúde , Heterozigoto , Humanos , Deficiência Intelectual/genética , Masculino
12.
DNA Cell Biol ; 40(5): 706-712, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33691472

RESUMO

Serine protease inhibitor b5 (SERPINB5) is a tumor suppressor gene that plays a critical role in various cellular processes. In gallbladder cancer (GBC), SERPINB5's aberrant expression is reported but its role in genetic predisposition is not known. We enrolled 270 cases and 296 controls and genotyped them for single nucleotide polymorphisms (SNPs) using direct DNA sequencing, followed by genotype-phenotype analysis in GBC and other cancer cell lines. Luciferase assay was done to determine the role of rs2289521 SNP on expression regulation. We found that two SERPINB5 variants rs2289519 and rs2289521 are significantly associated with GBC and contribute to genetic predisposition. The TT genotype of variant rs2289519 was found to be significantly associated (p = 0.008) with GBC in a recessive model. C allele of rs2289521 increased the risk for GBC significantly at genotypic (CT, p = 0.026) and allelic (p = 0.04) levels. In silico analysis and luciferase assay uncovered the probable regulatory role of the rs2289521 variant on expression. Genotype-phenotype correlation in GBC and breast cancer cell lines showed reduced expression of SERPINB5 in the presence of C allele that was consistent with the result of luciferase assay. Overall, our study reveals the genetic association of two SERPINB5 variants with GBC and rs2289521's possible role in the regulation of expression.


Assuntos
Neoplasias da Vesícula Biliar/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Serpinas/genética , Alelos , Linhagem Celular Tumoral , Feminino , Genes Recessivos , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Luciferases/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Fatores de Risco
15.
Am J Hum Genet ; 108(1): 186-193, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33417887

RESUMO

POLR3B encodes the second-largest catalytic subunit of RNA polymerase III, an enzyme involved in transcription. Bi-allelic pathogenic variants in POLR3B are a well-established cause of hypomyelinating leukodystrophy. We describe six unrelated individuals with de novo missense variants in POLR3B and a clinical presentation substantially different from POLR3-related leukodystrophy. These individuals had afferent ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy. Protein modeling and proteomic analysis revealed a distinct mechanism of pathogenicity; the de novo POLR3B variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability. We expand the spectrum of disorders associated with pathogenic variants in POLR3B to include a de novo heterozygous POLR3B-related disorder.


Assuntos
Ataxia/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , RNA Polimerase III/genética , Adolescente , Adulto , Ataxia Cerebelar/genética , Criança , Pré-Escolar , Feminino , Genes Recessivos/genética , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Proteômica/métodos , Adulto Jovem
16.
Mol Biol Evol ; 38(5): 1820-1836, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33480994

RESUMO

During range expansion, edge populations are expected to face increased genetic drift, which in turn can alter and potentially compromise adaptive dynamics, preventing the removal of deleterious mutations and slowing down adaptation. Here, we contrast populations of the European subspecies Arabidopsis lyrata ssp. petraea, which expanded its Northern range after the last glaciation. We document a sharp decline in effective population size in the range-edge population and observe that nonsynonymous variants segregate at higher frequencies. We detect a 4.9% excess of derived nonsynonymous variants per individual in the range-edge population, suggesting an increase of the genomic burden of deleterious mutations. Inference of the fitness effects of mutations and modeling of allele frequencies under the explicit demographic history of each population predicts a depletion of rare deleterious variants in the range-edge population, but an enrichment for fixed ones, consistent with the bottleneck effect. However, the demographic history of the range-edge population predicts a small net decrease in per-individual fitness. Consistent with this prediction, the range-edge population is not impaired in its growth and survival measured in a common garden experiment. We further observe that the allelic diversity at the self-incompatibility locus, which ensures strict outcrossing and evolves under negative frequency-dependent selection, has remained unchanged. Genomic footprints indicative of selective sweeps are broader in the Northern population but not less frequent. We conclude that the outcrossing species A. lyrata ssp. petraea shows a strong resilience to the effect of range expansion.


Assuntos
Arabidopsis/genética , Carga Genética , Dispersão Vegetal , Fluxo Gênico , Genes Recessivos , Aptidão Genética , Genoma de Planta , Dinâmica Populacional , Seleção Genética
17.
Nat Commun ; 12(1): 627, 2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504798

RESUMO

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.


Assuntos
Deficiências do Desenvolvimento/genética , Genes Ligados ao Cromossomo X , Doenças Genéticas Ligadas ao Cromossomo X/genética , Variação Genética , Cromossomos Humanos X/genética , Feminino , Genes Recessivos , Humanos , Padrões de Herança/genética , Masculino , Herança Multifatorial/genética , Mutação/genética , Fenótipo , Caracteres Sexuais
18.
Hum Genet ; 140(6): 915-931, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33496845

RESUMO

Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.


Assuntos
Substituição de Aminoácidos , Cromossomos Humanos Par 4/química , Células Ciliadas Auditivas Internas/metabolismo , Perda Auditiva Neurossensorial/genética , Proteínas de Membrana/genética , Mutação Puntual , Tetraspaninas/genética , Adulto , Alelos , Animais , Sequência de Bases , Mapeamento Cromossômico , Consanguinidade , Feminino , Expressão Gênica , Genes Recessivos , Células Ciliadas Auditivas Internas/patologia , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Proteínas de Membrana/deficiência , Camundongos , Linhagem , Tetraspaninas/deficiência , Sequenciamento Completo do Exoma , Peixe-Zebra
19.
JCI Insight ; 6(2)2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33491668

RESUMO

BACKGROUNDRecessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease that causes severe mucocutaneous fragility due to mutations in COL7A1 (encoding type VII collagen [C7]). In this phase I/IIa trial, we evaluated the safety and possible clinical efficacy of intravenous infusion of allogeneic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in patients with RDEB.METHODSFour adult and two pediatric patients with RDEB were treated with 3 intravenous injections of hUCB-MSCs (1 × 106 to 3 × 106 cells/kg) every 2 weeks and followed up for 8-24 months after treatment. The primary endpoint was safety. Secondary endpoints related to efficacy included clinical parameters, such as disease severity score, wound assessment, itch and pain score, and quality of life. C7 expression levels and inflammatory infiltrates in the skin, as well as serum levels of inflammatory markers and neuropeptides, were also assessed.RESULTSIntravenous hUCB-MSC infusions were well tolerated, without serious adverse events. Improvements in the Birmingham Epidermolysis Bullosa Severity Score, body surface area involvement, blister counts, pain, pruritus, and quality of life were observed with maximal effects at 56-112 days after treatment. hUCB-MSC administration induced M2 macrophage polarization and reduced mast cell infiltration in RDEB skin. Serum levels of substance P were decreased after therapy. Increased C7 expression was observed at the dermoepidermal junction in 1 of 6 patients at day 56.CONCLUSIONTo the best of our knowledge, this is the first clinical trial of systemic administration of allogeneic hUCB-MSCs in patients with RDEB, demonstrating safety and transient clinical benefits.TRIAL REGISTRATIONClinicalTrials.gov NCT04520022.FUNDINGThis work was supported by Daewoong Pharmaceutical Co. Ltd. and Kangstem Biotech Co. Ltd.


Assuntos
Epidermólise Bolhosa Distrófica/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Adolescente , Adulto , Aloenxertos , Proteína C-Reativa/metabolismo , Criança , Colágeno Tipo VII/genética , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/patologia , Feminino , Genes Recessivos , Humanos , Infusões Intravenosas , Masculino , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Pessoa de Meia-Idade , Mutação , Medição da Dor , Prurido/terapia , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
20.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33408250

RESUMO

Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.


Assuntos
Imunidade/genética , Erros Inatos do Metabolismo/genética , Seleção Genética/genética , Genes Dominantes/genética , Genes Recessivos/genética , Variação Genética/genética , Variação Genética/imunologia , Humanos , Erros Inatos do Metabolismo/imunologia , Erros Inatos do Metabolismo/patologia
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