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1.
Am J Hum Genet ; 108(10): 1964-1980, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34547244

RESUMO

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.


Assuntos
Proteases Dependentes de ATP/genética , Proteases Dependentes de ATP/fisiologia , Anormalidades Craniofaciais/genética , Variações do Número de Cópias de DNA , Anormalidades do Olho/genética , Transtornos do Crescimento/genética , Hérnias Diafragmáticas Congênitas/genética , Luxação Congênita de Quadril/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/fisiologia , Mutação de Sentido Incorreto , Osteocondrodisplasias/genética , Anormalidades Dentárias/genética , Animais , Estudos de Casos e Controles , Estudos de Coortes , Anormalidades Craniofaciais/patologia , Anormalidades do Olho/patologia , Feminino , Transtornos do Crescimento/patologia , Hérnias Diafragmáticas Congênitas/patologia , Luxação Congênita de Quadril/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteocondrodisplasias/patologia , Linhagem , Anormalidades Dentárias/patologia
2.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200910

RESUMO

To increase the half-life of growth hormones, we proposed its long-lasting regulation through the ubiquitin-proteasome system (UPS). We identified lysine residues (K67, K141, and K166) that are involved in the ubiquitination of human growth hormone (hGH) using ubiquitination site prediction programs to validate the ubiquitination sites, and then substituted these lysine residues with arginine residues. We identified the most effective substituent (K141R) to prevent ubiquitination and named it AUT-hGH. hGH was expressed and purified in the form of hGH-His, and ubiquitination was first verified at sites containing K141 in the blood stream. Through the study, we propose that AUT-hGH with an increased half-life could be used as a long-lasting hGH in the blood stream.


Assuntos
Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Ubiquitinação , Animais , Citoplasma/metabolismo , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/patologia , Células HEK293 , Meia-Vida , Humanos , Masculino , Camundongos , Células NIH 3T3 , Ratos , Ratos Sprague-Dawley
3.
PLoS One ; 16(5): e0249776, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34038415

RESUMO

Stunting undermines economic growth by perpetuating the vicious cycle of poverty and labour market performance. Studies have captured the trend in stunting and present distributional evidence of policy effects in the country contexts. We identify the determinants of U5 (under 5 years of age) malnutrition for the poor and the Nonpoor and compare the distribution of stunting at four time points (2000, 2005, 2010 and 2015) over a 15-year period between different groups of population. Further, we decompose the gap in malnutrition into causes of differences in stunting between worse-off and better-off socioeconomic groups of the population and estimate the magnitude of distributional differences in stunting between two socioeconomic groups. We also present the inequality trend over time that provides insights into the dynamicity of the effect of different determinants on stunting at different time points. Using 35,490 observations from Armenian Demographic and Health Survey Data [four waves: Year2015,9533; Year2010,8644; Year2005,8919; Year2000,8334], we apply regression-based decomposition method and inequality measures to identify the determinants of malnutrition and distribution of stunting between and within socioeconomic groups. Although the proportional difference in prevalence of stunting between worse-off and better-off children of 13 months and above are reduced by 9.5% in 2015 compared to 2000, the association between socioeconomic position and stunting is statistically significant among children aged 13 months and above in 2000, as well as among children of 36 months and above in 2015. This study demonstrates that the less of socioeconomic distribution of the population, but rather more of the effect from in-country region and settlement of residence are significantly associated with stunting. The approach of our analysis is potentially also a useful tool to generate evidence for decision making towards achieving SDGs 2.2. We conclude that development in childhood is not independent from the distributional effect of region specific development initiatives. Understanding the regional characteristics and resources allocated for the maternal and child health is the necessity to address stunting.


Assuntos
Transtornos do Crescimento/epidemiologia , Desnutrição/epidemiologia , Armênia/epidemiologia , Pré-Escolar , Bases de Dados Factuais , Feminino , Transtornos do Crescimento/patologia , Inquéritos Epidemiológicos , Humanos , Lactente , Masculino , Desnutrição/diagnóstico , Classe Social
4.
ScientificWorldJournal ; 2021: 5591251, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981185

RESUMO

OSA pediatric subjects suffer from episodes of upper airway obstruction that can be partial or complete, with atypical sleep patterns and blood-gas level alteration. If poor treated and/or diagnosed, it can cause cardiovascular disease, learning difficulties, behavioural issues, and retardation of growth. In the literature, there are conflicting evidence about OSA assessment and treatment in pediatric age, so the aim of this paper is to highlight the multidisciplinary approach in the management of sleep disorders, stressing the role of the pediatric dentist in both diagnosing and treating the OSAS in children, according to the current evidence of the treatment options effectiveness of the syndrome itself. Conclusions. Scientific evidence shows that OSAS management requires a multidisciplinary approach in order to make an early diagnosis and a correct treatment plan. The orthodontic treatment approach includes orthopedic maxillary expansion and mandibular advancement using intraoral appliances. Hence, the orthodontist and the pediatric dentist play an important role not only in early diagnosis but also in the treatment of pediatric OSAS.


Assuntos
Obstrução das Vias Respiratórias/diagnóstico , Doenças Cardiovasculares/diagnóstico , Transtornos do Crescimento/diagnóstico , Avanço Mandibular/métodos , Ortodontia Corretiva/métodos , Apneia Obstrutiva do Sono/diagnóstico , Obstrução das Vias Respiratórias/complicações , Obstrução das Vias Respiratórias/patologia , Obstrução das Vias Respiratórias/cirurgia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/prevenção & controle , Criança , Odontólogos , Diagnóstico Precoce , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/patologia , Transtornos do Crescimento/prevenção & controle , Humanos , Ortodontistas , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/patologia , Apneia Obstrutiva do Sono/cirurgia
5.
Am J Hum Genet ; 108(6): 1053-1068, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33909990

RESUMO

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.


Assuntos
Anormalidades Múltiplas/patologia , Adenosina Trifosfatases/genética , Anormalidades Craniofaciais/patologia , Metilação de DNA , Epigênese Genética , Transtornos do Crescimento/patologia , Comunicação Interventricular/patologia , Mutação , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Anormalidades Múltiplas/genética , Estudos de Casos e Controles , Estudos de Coortes , Anormalidades Craniofaciais/genética , Feminino , Predisposição Genética para Doença , Transtornos do Crescimento/genética , Comunicação Interventricular/genética , Humanos , Recém-Nascido , Masculino , Transtornos do Neurodesenvolvimento/genética
6.
J Pediatr Endocrinol Metab ; 34(5): 547-557, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-33851527

RESUMO

OBJECTIVES: We performed a cross-sectional study on anthropometric and laboratory characteristics of inhabitants of Rampasasa (Flores, Indonesia). Adults were categorised according to ancestry into three groups: pygmoid (P/P, offspring of pygmoid parents, n=8), mixed pygmoid (P/N, offspring of pygmoid and non-pygmoid parents, n=12) and non-pygmoid (N/N, n=10). Children (n=28) were P/N. METHODS: Measurements included height, weight, sitting height, arm span, head circumference, haematological analysis and serum albumin, calcium, vitamin D, insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3). Pubertal stage and bone age was assessed in children. Anthropometric data were expressed as standard deviation score (SDS) for age. IGF-I, IGFBP-3 and IGF-I/IGFBP-3 ratio were expressed as SDS for age, bone age and pubertal stage. RESULTS: Mean height SDS showed a gradient from P/P (-4.0) via P/N (-3.2) to N/N (-2.3) (-3.4, -3.1 and -2.2 adjusted for age-associated shrinking). Sitting height and head circumference showed similar gradients. Serum IGF-I SDS was similar among groups (approximately -1 SDS). IGFBP-3 SDS tended toward a gradient from P/P (-1.9) via P/N (-1.5) to N/N (-1.1), but IGF-I/IGFBP-3 ratio was normal in all groups. In P/P and P/N, mean head circumference SDS was >2 SD greater than mean height SDS. Children showed a progressive growth failure and bone age delay, delayed female pubertal onset and an initial low serum IGF-I, normal IGFBP-3 and low IGF-I/IGFBP-3 ratio. CONCLUSIONS: P/P showed proportionate short stature with relative macrocephaly and relatively low IGFBP-3; P/N presented an intermediate pattern. P/N children were progressively short, showed delayed skeletal maturation, delayed puberty in girls and low IGF-I and IGF-I/IGFBP-3.


Assuntos
Índice de Massa Corporal , Peso Corporal , Doenças Ósseas/epidemiologia , Transtornos do Crescimento/epidemiologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Adulto , Antropometria , Doenças Ósseas/metabolismo , Doenças Ósseas/patologia , Pré-Escolar , Estudos Transversais , Feminino , Seguimentos , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/patologia , Humanos , Indonésia/epidemiologia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prognóstico
7.
J Pediatr Endocrinol Metab ; 34(5): 559-565, 2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-33851794

RESUMO

OBJECTIVES: Childhood growth influences their social and psychological behavior, and abnormal growth may reflect underlying pathological etiologies. It is important to diagnose children with short stature as early as possible to be able to manage treatable causes. We aim to study etiologies and characteristics of short stature in children in Jordan. METHODS: This is a cross-sectional retrospective review of the medical records of children diagnosed with short stature at a referral university hospital. Clinical characteristics, auxological, laboratory, and radiological investigations were collected and analyzed. RESULTS: Among a total of 551 children diagnosed with short stature, the number of boys was significantly higher than girls, 304 (55.2%) and 247 (44.8%), respectively with a p-value of 0.015. Average age at presentation for all patients was 10.24 ± 3.23, with no significant difference between boys and girls. Pathological etiology was higher than normal variants 55.7 and 44.3%, respectively with p=0.007. Constitutional delay of growth and puberty (CDGP) was the most frequent cause in the normal variant group, 59.8%. Among the pathological group, the most common etiology was growth hormone deficiency (32.2%) with mean age of presentation of 9.40 years and was not significantly different from the age in other etiological groups, 9.44 years and p=0.931. CONCLUSIONS: Growth monitoring of children should start at an early age for boys and girls. Referral to the pediatric endocrine clinic should be considered when growth problems are suspected for accurate diagnosis and etiology profiling.


Assuntos
Estatura , Nanismo Hipofisário/complicações , Transtornos do Crescimento/etiologia , Criança , Estudos Transversais , Feminino , Seguimentos , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/patologia , Humanos , Jordânia/epidemiologia , Masculino , Prognóstico , Estudos Retrospectivos
8.
Am J Med Genet A ; 185(6): 1649-1665, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33783954

RESUMO

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS.


Assuntos
Predisposição Genética para Doença , Transtornos do Crescimento/genética , Histona-Lisina N-Metiltransferase/genética , Hipertricose/congênito , Deficiência Intelectual/genética , Proteína de Leucina Linfoide-Mieloide/genética , /genética , Constipação Intestinal/epidemiologia , Constipação Intestinal/genética , Constipação Intestinal/patologia , Insuficiência de Crescimento/epidemiologia , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Estudos de Associação Genética , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/patologia , Humanos , Hipertricose/epidemiologia , Hipertricose/genética , Hipertricose/patologia , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/patologia , Mutação com Perda de Função/genética , Estudos Retrospectivos , /genética
9.
Am J Med Genet A ; 185(5): 1430-1436, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33683022

RESUMO

Activating variants in the platelet-derived growth factor receptor ß gene (PDGFRB) have been associated with Kosaki overgrowth syndrome, infantile myofibromatosis, and Penttinen premature aging syndrome. A recently described phenotype with fusiform aneurysm has been associated with mosaic PDGFRB c.1685A > G p.(Tyr562Cys) variant. Few reports however have examined the vascular phenotypes and mosaic effects of PDGFRB variants. We describe clinical characteristics of two patients with a recurrent mosaic PDGFRB p.(Tyr562Cys) variant identified via next-generation sequencing-based genetic testing. We observed intracranial fusiform aneurysm in one patient and found an additional eight patients with aneurysms and phenotypes associated with PDGFRB-activating variants through literature search. The conditions caused by PDGFRB-activating variants share overlapping features including overgrowth, premature aged skin, and vascular malformations including aneurysms. Aneurysms are progressive and can result in morbidities and mortalities in the absence of successful intervention. Germline and/or somatic testing for PDGFRB gene should be obtained when PDGFRB activating variant-related phenotypes are present. Whole-body imaging of the arterial tree and echocardiography are recommended after diagnosis. Repeating the imaging study within a 6- to 12-month period after detection is reasonable. Finally, further evaluation for the effectiveness and safety profile of kinase inhibitors in this patient population is warranted.


Assuntos
Aneurisma/genética , Transtornos do Crescimento/genética , Aneurisma Intracraniano/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Adulto , Senilidade Prematura/genética , Aneurisma/epidemiologia , Aneurisma/patologia , Criança , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Aneurisma Intracraniano/epidemiologia , Aneurisma Intracraniano/patologia , Masculino , Pessoa de Meia-Idade , Mosaicismo , Fenótipo , Anormalidades da Pele/epidemiologia , Anormalidades da Pele/genética , Anormalidades da Pele/patologia , Adulto Jovem
10.
Am J Med Genet A ; 185(4): 1312-1316, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33528093

RESUMO

Ayme Gripp syndrome (OMIM#601088) is a multisystem disorder caused by heterozygous variation in the MAF (OMIM*177075). The typical phenotype comprises a tetralogy of congenital cataract, sensory neural hearing loss, a characteristic facial appearance along with neurodevelopment abnormalities. Exact prevalence estimates are unknown. Only 21 individuals representing 19 families have been reported in the literature till date. To the best of our knowledge, this is the first detailed case report of a boy with Ayme Gripp syndrome from our country. Although he had multiple typical features of the syndrome along with a known pathogenic variation in the MAF, cataract was not observed in him at the age of seven years.


Assuntos
Catarata/genética , Transtornos do Crescimento/genética , Perda Auditiva Neurossensorial/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Proto-Oncogênicas c-maf/genética , Catarata/patologia , Pré-Escolar , Facies , Transtornos do Crescimento/patologia , Perda Auditiva Neurossensorial/patologia , Heterozigoto , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/patologia , Masculino , Mutação/genética , Transtornos do Neurodesenvolvimento/patologia , Fenótipo
11.
J Clin Endocrinol Metab ; 106(6): 1742-1749, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33570564

RESUMO

CONTEXT: Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X, and XI are present. Defects in collagen genes cause heterogeneous syndromic disorders frequently associated with short stature. Less is known about oligosymptomatic collagenopathies. OBJECTIVE: This work aims to evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response. METHODS: Eighty-seven FSS children (pretreatment height ≤ -2 SD both in the patient and his or her shorter parent) treated with GH were included in the study. Next-generation sequencing was performed to search for variants in the COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, and COL11A2 genes. The results were evaluated using American College of Medical Genetics and Genomics guidelines. The GH treatment response of affected children was retrospectively evaluated. RESULTS: A likely pathogenic variant in the collagen gene was found in 10 of 87 (11.5%) children. Detailed examination described mild asymmetry with shorter limbs and mild bone dysplasia signs in 2 of 10 and 4 of 10 affected children, respectively. Their growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after 1 year of treatment. Their height improved from a median of -3.1 SD to -2.6 SD and to -2.2 SD after 1 and 3 years of therapy, respectively. The final height reached by 4 of 10 children differed by -0.67 to +1.0 SD and -0.45 to +0.5 SD compared to their pretreatment height and their affected untreated parent's height, respectively. CONCLUSION: Oligosymptomatic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising.


Assuntos
Colágeno/genética , Transtornos do Crescimento , Lâmina de Crescimento/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Colágeno/deficiência , Colágeno Tipo XI/genética , República Tcheca/epidemiologia , Bases de Dados Factuais , Feminino , Estudos de Associação Genética , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Lâmina de Crescimento/crescimento & desenvolvimento , Lâmina de Crescimento/metabolismo , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Fenótipo , Estudos Retrospectivos , Adulto Jovem
12.
Nat Microbiol ; 6(4): 445-454, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33589804

RESUMO

Environmental enteropathy is a major contributor to growth faltering in millions of children in Africa and South Asia. We carried out a longitudinal, observational and interventional study in Lusaka, Zambia, of 297 children with stunting (aged 2-17 months at recruitment) and 46 control children who had good growth (aged 1-5 months at recruitment). Control children contributed data only at baseline. Children were provided with nutritional supplementation of daily cornmeal-soy blend, an egg and a micronutrient sprinkle, and were followed up to 24 months of age. Children whose growth did not improve over 4-6 months of nutritional supplementation were classified as having non-responsive stunting. We monitored microbial translocation from the gut lumen to the bloodstream in the cohort with non-responsive stunting (n = 108) by measuring circulating lipopolysaccharide (LPS), LPS-binding protein and soluble CD14 at baseline and when non-response was declared. We found that microbial translocation decreased with increasing age, such that LPS declined in 81 (75%) of 108 children with non-responsive stunting, despite sustained pathogen pressure and ongoing intestinal epithelial damage. We used confocal laser endomicroscopy and found that mucosal leakiness also declined with age. However, expression of brush border enzyme, nutrient transporter and mucosal barrier genes in intestinal biopsies did not change with age or correlate with biomarkers of microbial translocation. We propose that environmental enteropathy arises through adaptation to pathogen-mediated epithelial damage. Although environmental enteropathy reduces microbial translocation, it does so at the cost of impaired growth. The reduced epithelial surface area imposed by villus blunting may explain these findings.


Assuntos
Adaptação Fisiológica , Transtornos do Crescimento/patologia , Intestino Delgado/microbiologia , Intestino Delgado/patologia , Translocação Bacteriana , Biomarcadores/sangue , Enterite/epidemiologia , Enterite/microbiologia , Enterite/patologia , Feminino , Seguimentos , Perfilação da Expressão Gênica , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/microbiologia , Infecções por HIV/epidemiologia , Infecções por HIV/microbiologia , Infecções por HIV/patologia , Humanos , Lactente , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Intestino Delgado/metabolismo , Masculino , Zâmbia/epidemiologia
13.
Eur J Med Genet ; 64(4): 104182, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33639314

RESUMO

Disruption of the initiation of DNA replication is significantly associated with Meier-Gorlin syndrome (MGORS), an autosomal recessive condition of reduced growth, microtia and patellar a/hypoplasia. Biallelic mutations in CDC45, a member of the pre-initiation complex in DNA replication, cause a spectrum of phenotypes ranging from MGORS with craniosynostosis, through to isolated short stature and craniosynostosis. Here we report two affected sibs with MGORS and craniosynostosis, with biallelic variants in CDC45 identified by 10X Chromium whole genome sequencing. One variant is a frameshift mutation, predicted to be pathogenic, and is inherited in trans with a synonymous variant in a non-canonical exon (exon 7) of CDC45. An in vitro splicing assay showed that while the canonical CDC45 exon 6-exon 8 transcript (with skipping of exon 7; numbering as per NM001178010.2) remained as the predominant transcript, the variant allele induced the use of novel splice acceptor sites in intron 6, all of which produced transcripts harbouring premature stop codons. This perturbation of canonical splicing provides evidence that this synonymous variant is indeed a deleterious alteration in this family. This report adds to the initial patient cohort in which several synonymous variants were also described, further highlighting the contribution of this variant type in CDC45. It also reiterates the true potential pathogenicity of synonymous variants, which is a mutation type that is commonly ignored in variant prioritization strategies.


Assuntos
Proteínas de Ciclo Celular/genética , Microtia Congênita/genética , Craniossinostoses/genética , Transtornos do Crescimento/genética , Micrognatismo/genética , Mutação , Patela/anormalidades , Sítios de Splice de RNA , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Criança , Pré-Escolar , Microtia Congênita/patologia , Craniossinostoses/patologia , Éxons , Transtornos do Crescimento/patologia , Humanos , Masculino , Micrognatismo/patologia , Patela/patologia , Linhagem
14.
Sci Rep ; 11(1): 1619, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452336

RESUMO

Numerous population-based studies have documented high prevalence of aflatoxin associated childhood stunting in low income countries. We provide an estimate of the disease burden of aflatoxin related stunting using data from the four African countries. For this empirical analysis, we obtained blood aflatoxin albumin adduct biomarker based exposure data as measured using ELISA technique and anthropometric measurement data from surveys done over a 12-year period from 2001 to 2012 in four low income countries in Africa. We used these data to calculate population attributable risk (PAR), life time disease burden for children under five by comparing two groups of stunted children using both prevalence and incidence-based approaches. We combined prevalence estimates with a disability weight, measuring childhood stunting and co-occurrence of stunting-underweight to produce years lived with disability. Using a previously reported mortality, years of life lost were estimated. We used probabilistic analysis to model these associations to estimate the disability-adjusted life-years (DALYs), and compared these with those given by the Institute for Health Metrics and Evaluation's Global Burden of Disease (GBD) 2016 study. The PAR increased from 3 to 36% for aflatoxin-related stunting and 14-50% for co-occurrence of stunting and underweight. Using prevalence-based approach, children with aflatoxin related stunting resulted in 48,965.20 (95% uncertainty interval (UI): 45,868.75-52,207.53) DALYs per 100,000 individuals. Children with co-occurrence of stunting and underweight due to exposure to aflatoxin resulted in 40,703.41 (95% UI: 38,041.57-43,517.89) DALYs per 100,000 individuals. Uncertainty analysis revealed that reducing aflatoxin exposure in high exposure areas upto non-detectable levels could save the stunting DALYs up to 50%. The burden of childhood all causes stunting is greater in countries with higher aflatoxin exposure such as Benin. In high exposure areas, these results might help guide research protocols and prioritisation efforts and focus aflatoxin exposure reduction. HEFCE Global Challenge Research Fund Aflatoxin project.


Assuntos
Aflatoxinas/efeitos adversos , Efeitos Psicossociais da Doença , Transtornos do Crescimento/patologia , Aflatoxinas/sangue , Albuminas , Benin , Pré-Escolar , Feminino , Gâmbia , Transtornos do Crescimento/economia , Transtornos do Crescimento/etiologia , Humanos , Lactente , Masculino , Anos de Vida Ajustados por Qualidade de Vida , Fatores de Risco , Tanzânia , Togo
15.
J Med Genet ; 58(3): 173-176, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32447323

RESUMO

BACKGROUND: The chromosomal region 11p15.5 harbours two imprinting centres (H19/IGF2:IG-DMR/IC1, KCNQ1OT1:TSS-DMR/IC2). Molecular alterations of the IC2 are associated with Beckwith-Wiedemann syndrome (BWS), whereas only single patients with growth retardation and Silver-Russell syndrome (SRS) features have been reported. CNVs in 11p15.5 account for less than 1% of patients with BWS and SRS, and they mainly consist of duplications of both ICs either affecting the maternal (SRS) or the paternal (BWS) allele. However, this correlation does not apply to smaller CNVs, which are associated with diverse clinical outcomes. METHODS AND RESULTS: We identified a family with a 132 bp deletion within the KCNQ1OT1 gene, associated with growth retardation in case of paternal transmission but a normal phenotype when maternally inherited. Comparison of molecular and clinical data with cases from the literature helped to delineate its functional relevance. CONCLUSION: Microdeletions within the paternal IC2 affecting the KCNQ1OT1 gene have been described in only five families, and they all include the differentially methylated region KCNQ1OT1:TSS-DMR/IC2 and parts of the KCNQ1 gene. However, these deletions have different impacts on the expression of both genes and the cell-cycle inhibitor CDKN1C. They thereby cause different phenotypes. The 132 bp deletion is the smallest deletion in the IC2 reported so far. It does not affect the IC2 methylation in general and the coding sequence of the KCNQ1 gene. Thus, the deletion is only associated with a growth retardation phenotype when paternally transmitted but not with other clinical features in case of maternal inheritance as observed for larger deletions.


Assuntos
Impressão Genômica/genética , Transtornos do Crescimento/genética , Canal de Potássio KCNQ1/genética , Síndrome de Beckwith-Wiedemann/epidemiologia , Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/patologia , Pré-Escolar , Cromossomos Humanos Par 11/genética , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , Feminino , Predisposição Genética para Doença , Alemanha , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/patologia , Humanos , Lactente , Fator de Crescimento Insulin-Like II/genética , Linhagem , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , RNA Longo não Codificante/genética , Síndrome de Silver-Russell/epidemiologia , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/patologia
16.
Eur J Hum Genet ; 29(1): 110-121, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32647378

RESUMO

SHOX haploinsufficiency causes 70-90% of Léri-Weill dyschondrosteosis (LWD) and 2-10% of idiopathic short stature (ISS). Deletions removing the entire gene or enhancers and point mutations in the coding region represent a well-established cause of haploinsufficiency. During diagnostic genetic testing on ISS/LWD patients, in addition to classic SHOX defects, five 5'UTR variants (c.-58G > T, c.-55C > T, c.-51G > A, c.-19G > A, and c.-9del), were detected whose pathogenetic role was unclear and were thus classified as VUS (Variants of Uncertain Significance). The purpose of the present study was to investigate the role of these noncoding variations in SHOX haploinsufficiency. The variants were tested for their ability to interfere with correct gene expression of a regulated reporter gene (luciferase assay). The negative effect on the mRNA splicing predicted in silico for c.-19G > A was assayed in vitro through a minigene splicing assay. The luciferase assay showed that c.-51G > A, c.-19G > A, and c.-9del significantly reduce luciferase activity by 60, 35, and 40% at the homozygous state. Quantification of the luciferase mRNA showed that c.-51G > A and c.-9del might interfere with the correct SHOX expression mainly at the post-transcriptional level. The exon trapping assay demonstrated that c.-19G > A determines the creation of a new branch site causing an aberrant mRNA splicing. In conclusion, this study allowed us to reclassify two of the 5'UTR variants identified during SHOX diagnostic screening as likely pathogenic, one remains as a VUS, and two as likely benign variants. This analysis for the first time expands the spectrum of the genetic causes of SHOX haploinsufficiency to noncoding variations in the 5'UTR.


Assuntos
Regiões 5' não Traduzidas , Transtornos do Crescimento/genética , Osteocondrodisplasias/genética , Proteína de Homoeobox de Baixa Estatura/genética , Adolescente , Linhagem Celular Tumoral , Criança , Feminino , Transtornos do Crescimento/patologia , Haploinsuficiência , Humanos , Masculino , Mutação , Osteocondrodisplasias/patologia , Splicing de RNA , Proteína de Homoeobox de Baixa Estatura/metabolismo
17.
Am J Med Genet A ; 185(1): 119-133, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33098347

RESUMO

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.


Assuntos
Eczema/diagnóstico , Eczema/genética , Predisposição Genética para Doença , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Histona Desacetilases/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Microcefalia/diagnóstico , Microcefalia/genética , Proteínas Repressoras/genética , Adolescente , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Eczema/patologia , Exoma/genética , Facies , Feminino , Genoma Humano/genética , Genômica/métodos , Transtornos do Crescimento/patologia , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Microcefalia/patologia , Fenótipo , Sequenciamento Completo do Exoma
18.
J Cell Physiol ; 236(4): 2631-2648, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32853405

RESUMO

Individuals with postnatal growth retardation (PGR) are prone to developing chronic diseases. Abnormal development in small intestine is casually implicated in impaired growth. However, the exact mechanism is still implausible. In this present study, PGR piglets (aged 42 days) were employed as a good model to analyze developmental changes in intestinal mucosal barrier function. Our data demonstrated that PGR piglets exhibited impaired jejunal and ileal epithelial villous morphology and permeability, accompanied by decreased cell proliferation ability and increased apoptosis rate. In addition, the expression of tight junction proteins (ZO-1, claudin 1, and occludin) and E-cadherin was markedly inhibited by PGR. The expression of P-glycoprotein was significantly reduced in PGR piglets, as well as decreased activity of lysozyme. Moreover, the mRNA abundance and content of inflammatory cytokines were significantly increased in the intestinal mucosa and plasma of PGR piglets, respectively. PGR also contributed to lower level of sIgA, and higher level of CD68-positive rate, ß-defensins, and protein expression involved p38 MAPK/NF-κB pathway. Furthermore, PGR altered the intestinal microbial community such as decreased genus Alloprevotella and Oscillospira abundances, and led to lower microbial-derived butyrate production, which may be potential targets for treatment. Collectively, our findings indicated that the intestinal mucosal barrier function of PGR piglets could develop the nutritional intervention strategies in prevention and treatment of the intestinal mucosal barrier dysfunction in piglets and humans.


Assuntos
Transtornos do Crescimento/metabolismo , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Animais Recém-Nascidos , Apoptose , Bactérias/metabolismo , Butiratos/metabolismo , Proliferação de Células , Citocinas/metabolismo , Modelos Animais de Doenças , Microbioma Gastrointestinal , Transtornos do Crescimento/microbiologia , Transtornos do Crescimento/patologia , Transtornos do Crescimento/fisiopatologia , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/crescimento & desenvolvimento , Mucosa Intestinal/microbiologia , Mucosa Intestinal/ultraestrutura , Intestino Delgado/crescimento & desenvolvimento , Intestino Delgado/microbiologia , Intestino Delgado/ultraestrutura , Muramidase/metabolismo , NF-kappa B/metabolismo , Permeabilidade , Sus scrofa , Proteínas de Junções Íntimas/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Can J Physiol Pharmacol ; 99(1): 56-63, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32799662

RESUMO

Epigenetic DNA methylation (1-carbon metabolism) is crucial for gene imprinting/off-printing that ensures epigenetic memory but also generates a copious amount of homocysteine (Hcy), unequivocally. That is why during pregnancy, expectant mothers are recommended "folic acid" preemptively to avoid birth defects in the young ones because of elevated Hcy levels (i.e., hyperhomocysteinemia (HHcy)). As we know, children born with HHcy have several musculoskeletal abnormalities, including growth retardation. Here, we focus on the gut-dysbiotic microbiome implication(s) that we believe instigates the "1-carbon metabolism" and HHcy causing growth retardation along with skeletal muscle abnormalities. We test our hypothesis whether high-methionine diet (HMD) (an amino acid that is high in red meat), a substrate for Hcy, can cause skeletal muscle and growth retardation, and treatment with probiotics (PB) to mitigate skeletal muscle dysfunction. To test this, we employed cystathionine ß-synthase, CBS deficient mouse (CBS+/-) fed with/without HMD and with/without a probiotic (Lactobacillus rhamnosus) in drinking water for 16 weeks. Matrix metalloproteinase (MMP) activity, a hallmark of remodeling, was measured by zymography. Muscle functions were scored via electric stimulation. Our results suggest that compared to the wild-type, CBS+/- mice exhibited reduced growth phenotype. MMP-2 activity was robust in CBS+/- and HMD effects were successfully attenuated by PB intervention. Electrical stimulation magnitude was decreased in CBS+/- and CBS+/- treated with HMD. Interestingly; PB mitigated skeletal muscle growth retardation and atrophy. Collectively, results imply that individuals with mild/moderate HHcy seem more prone to skeletal muscle injury and its dysfunction.


Assuntos
Disbiose/complicações , Transtornos do Crescimento/prevenção & controle , Hiper-Homocisteinemia/complicações , Músculo Esquelético/patologia , Probióticos/administração & dosagem , Animais , Cistationina beta-Sintase/deficiência , Cistationina beta-Sintase/genética , Metilação de DNA , Modelos Animais de Doenças , Disbiose/metabolismo , Disbiose/microbiologia , Disbiose/terapia , Epigênese Genética , Feminino , Microbioma Gastrointestinal/fisiologia , Transtornos do Crescimento/sangue , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/patologia , Homocisteína/sangue , Homocisteína/metabolismo , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/genética , Hiper-Homocisteinemia/metabolismo , Lactobacillus rhamnosus , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metionina/administração & dosagem , Metionina/metabolismo , Camundongos , Camundongos Transgênicos , Músculo Esquelético/metabolismo
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