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1.
Eur J Endocrinol ; 181(5): K43-K53, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31539878

RESUMO

Background: IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe the fourth patient with severe short stature presenting a novel homozygous IGF1 gene mutation. Results: We report a boy born from consanguineous parents at 40 weeks of gestational age with intrauterine growth restriction and severe postnatal growth failure. Physical examination revealed proportionate short stature, microcephaly, facial dysmorphism, bilateral sensorineural deafness and mild global developmental delay. Basal growth hormone (GH) fluctuated from 0.2 to 29 ng/mL, while IGF1 levels ranged from -1.15 to 2.95 SDS. IGFBP3 was normal-high. SNP array delimited chromosomal regions of homozygosity, including 12q23.2 where IGF1 is located. IGF1 screening by HRM revealed a homozygous missense variant NM_000618.4(IGF1):c.322T>C, p.(Tyr108His). The change of the highly conserved Tyr60 in the mature IGF1 peptide was consistently predicted as pathogenic by multiple bioinformatic tools. Tyr60 has been described to be critical for IGF1 interaction with type 1 IGF receptor (IGF1R). In vitro, HEK293T cells showed a marked reduction of IGF1R phosphorylation after stimulation with serum from the patient as compared to sera from age-matched controls. Mutant IGF1 was also less efficient in inducing cell growth. Conclusion: The present report broadens the spectrum of clinical and biochemical presentation of homozygous IGF1 defects and underscores the variability these patients may present depending on the IGF/IGF1R pathway activity.


Assuntos
Transtornos do Crescimento/genética , Perda Auditiva Neurossensorial/genética , Fator de Crescimento Insulin-Like I/deficiência , Mutação de Sentido Incorreto/genética , Anormalidades Múltiplas/genética , Proliferação de Células , Biologia Computacional , Simulação por Computador , Retardo do Crescimento Fetal/genética , Células HEK293 , Homozigoto , Humanos , Lactente , Fator de Crescimento Insulin-Like I/genética , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Receptores de Somatomedina/genética , Tirosina/genética
2.
Nucleic Acids Res ; 47(16): 8720-8733, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31276587

RESUMO

Expression of human mitochondrial DNA is indispensable for proper function of the oxidative phosphorylation machinery. The mitochondrial genome encodes 22 tRNAs, 2 rRNAs and 11 mRNAs and their post-transcriptional modification constitutes one of the key regulatory steps during mitochondrial gene expression. Cytosine-5 methylation (m5C) has been detected in mitochondrial transcriptome, however its biogenesis has not been investigated in details. Mammalian NOP2/Sun RNA Methyltransferase Family Member 2 (NSUN2) has been characterized as an RNA methyltransferase introducing m5C in nuclear-encoded tRNAs, mRNAs and microRNAs and associated with cell proliferation and differentiation, with pathogenic variants in NSUN2 being linked to neurodevelopmental disorders. Here we employ spatially restricted proximity labelling and immunodetection to demonstrate that NSUN2 is imported into the matrix of mammalian mitochondria. Using three genetic models for NSUN2 inactivation-knockout mice, patient-derived fibroblasts and CRISPR/Cas9 knockout in human cells-we show that NSUN2 is necessary for the generation of m5C at positions 48, 49 and 50 of several mammalian mitochondrial tRNAs. Finally, we show that inactivation of NSUN2 does not have a profound effect on mitochondrial tRNA stability and oxidative phosphorylation in differentiated cells. We discuss the importance of the newly discovered function of NSUN2 in the context of human disease.


Assuntos
5-Metilcitosina/metabolismo , Eczema/genética , Transtornos do Crescimento/genética , Deficiência Intelectual/genética , Metiltransferases/genética , Microcefalia/genética , Processamento Pós-Transcricional do RNA , RNA Mitocondrial/genética , RNA de Transferência/genética , Animais , Sistemas CRISPR-Cas , Eczema/metabolismo , Eczema/patologia , Facies , Fibroblastos/metabolismo , Fibroblastos/patologia , Edição de Genes , Técnicas de Inativação de Genes , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/patologia , Células HEK293 , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Metilação , Metiltransferases/deficiência , Camundongos , Camundongos Knockout , Microcefalia/metabolismo , Microcefalia/patologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Conformação de Ácido Nucleico , Fosforilação Oxidativa , Cultura Primária de Células , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Mitocondrial/metabolismo , RNA de Transferência/metabolismo
3.
Cytogenet Genome Res ; 158(2): 56-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31158835

RESUMO

SHOX resides in the short arm pseudoautosomal region (PAR1) of the sex chromosomes and escapes X inactivation. SHOX haploinsufficiency underlies idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). A substantial percentage of cases with SHOX haploinsufficiency arise from pseudoautosomal copy number variations (CNVs) involving putative enhancer regions of SHOX. Our previous study using peripheral blood samples showed that some CpG dinucleotides adjacent to SHOX exon 1 were hypomethylated in a healthy woman and methylated in a woman with gross X chromosomal rearrangements. However, it remains unknown whether submicroscopic pseudoautosomal CNVs cause aberrant DNA methylation of SHOX-flanking CpG islands. In this study, we examined the DNA methylation status of SHOX-flanking CpG islands in 50 healthy individuals and 10 ISS/LWD patients with pseudoautosomal CNVs. In silico analysis detected 3 CpG islands within the 20-kb region from the translation start site of SHOX. Pyrosequencing and bisulfite sequencing of genomic DNA samples revealed that these CpG islands were barely methylated in peripheral blood cells and cultured chondrocytes of healthy individuals, as well as in peripheral blood cells of ISS/LWD patients with pseudoautosomal CNVs. These results, in conjunction with our previous findings, indicate that the DNA methylation status of SHOX-flanking CpG islands can be affected by gross X-chromosomal abnormalities, but not by submicroscopic CNVs in PAR1. Such CNVs likely disturb SHOX expression through DNA methylation-independent mechanisms, which need to be determined in future studies.


Assuntos
Metilação de DNA , Doenças Genéticas Ligadas ao Cromossomo X/genética , Transtornos do Crescimento/genética , Osteocondrodisplasias/genética , Proteína de Homoeobox de Baixa Estatura/genética , Adolescente , Adulto , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Condrócitos , Ilhas de CpG , Variações do Número de Cópias de DNA , Feminino , Humanos , Análise de Sequência de DNA
4.
Vet Clin North Am Food Anim Pract ; 35(2): 265-276, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31103180

RESUMO

Large offspring syndrome (LOS) is a fetal overgrowth condition in bovines most often observed in offspring conceived with the use of assisted reproductive technologies (ART). Phenotypes observed in LOS include, overgrowth, enlarged tongues, umbilical hernias, muscle and skeleton malformations, abnormal organ growth and placental development. Although LOS cases have only been reported to be associated with ART, fetal overgrowth can occur spontaneously in cattle (S-LOS). S-LOS refers to oversized calves that are born at normal gestation lengths. ART-induced LOS has been characterized as an epigenetic syndrome, more specifically, a loss-of-imprinting condition. We propose that S-LOS is also a loss-of-imprinting condition.


Assuntos
Doenças dos Bovinos/patologia , Transtornos do Crescimento/veterinária , Técnicas de Reprodução Assistida/veterinária , Animais , Síndrome de Beckwith-Wiedemann/genética , Síndrome de Beckwith-Wiedemann/patologia , Síndrome de Beckwith-Wiedemann/veterinária , Bovinos , Doenças dos Bovinos/etiologia , Doenças dos Bovinos/genética , Feminino , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Humanos , Gravidez , Técnicas de Reprodução Assistida/efeitos adversos
5.
Cytogenet Genome Res ; 157(3): 135-140, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30933954

RESUMO

We report a patient with developmental delay, brachydactyly type E, short stature, and tetralogy of Fallot. Brachydactyly-mental retardation syndrome (BDMR) was suspected based on the phenotype; however, array CGH excluded a 2q37 deletion, but identified a deletion encompassing the SHOX gene. BDMR is characterized by cognitive impairment, skeletal abnormalities involving hands and feet, short stature, and overweight. Most affected individuals carry relatively large 2q37 deletions encompassing HDAC4. This gene encodes a histone deacetylase involved in epigenetic regulation of cell growth and differentiation, specifically during endochondral bone formation in chondrocyte hypertrophy. Since SHOX haploinsufficiency can cause skeletal defects and short stature but would not fully explain the clinical picture of this patient, exome sequencing was performed, and a heterozygous HDAC8 frameshift mutation was identified. HDAC8 is a distinct histone deacetylase involved in cohesin recycling and is responsible for an X-linked dominant Cornelia de Lange-like phenotype. A new blended clinical phenotype may be explained by the result of a dual molecular diagnosis, which represents a combination of 2 independent genetic defects, with relevant implications for genetic counseling, clinical management, and prognosis.


Assuntos
Síndrome de Lange/diagnóstico , Mutação da Fase de Leitura , Deleção de Genes , Transtornos do Crescimento/diagnóstico , Histona Desacetilases/genética , Osteocondrodisplasias/diagnóstico , Proteínas Repressoras/genética , Proteína de Homoeobox de Baixa Estatura/genética , Criança , Hibridização Genômica Comparativa , Síndrome de Lange/genética , Feminino , Transtornos do Crescimento/genética , Haploinsuficiência , Humanos , Osteocondrodisplasias/genética , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
6.
Nat Commun ; 10(1): 1884, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015495

RESUMO

DNA methyltransferases (DNMTs) deposit DNA methylation, which regulates gene expression and is essential for mammalian development. Histone post-translational modifications modulate the recruitment and activity of DNMTs. The PWWP domains of DNMT3A and DNMT3B are posited to interact with histone 3 lysine 36 trimethylation (H3K36me3); however, the functionality of this interaction for DNMT3A remains untested in vivo. Here we present a mouse model carrying a D329A point mutation in the DNMT3A PWWP domain. The mutation causes dominant postnatal growth retardation. At the molecular level, it results in progressive DNA hypermethylation across domains marked by H3K27me3 and bivalent chromatin, and de-repression of developmental regulatory genes in adult hypothalamus. Evaluation of non-CpG methylation, a marker of de novo methylation, further demonstrates the altered recruitment and activity of DNMT3AD329A at bivalent domains. This work provides key molecular insights into the function of the DNMT3A-PWWP domain and role of DNMT3A in regulating postnatal growth.


Assuntos
Cromatina/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Transtornos do Crescimento/genética , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Mutação com Ganho de Função/fisiologia , Transtornos do Crescimento/patologia , Histonas/metabolismo , Humanos , Hipotálamo/metabolismo , Hipotálamo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação Puntual/fisiologia , Ligação Proteica/genética , Domínios Proteicos/genética , Processamento de Proteína Pós-Traducional/fisiologia
7.
J Hum Genet ; 64(7): 609-616, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31015584

RESUMO

Individuals affected with autosomal recessive cutis laxa type 2B and 3 usually show translucent skin with visible veins and abnormal elastic fibers, intrauterine and/or postnatal growth restriction and a typical triangular facial gestalt. Here we describe three unrelated individuals in whom such a cutis laxa syndrome was suspected, especially after electron microscopy revealed immature and less dense dermal elastic fibers in one of them. However, one of these children also displayed optic atrophy and two hypogammaglobulinemia. All had elevated liver enzymes and acute liver failure during febrile episodes leading to early demise in two of them. The only surviving patient had been treated with immunoglobulins. Through exome sequencing we identified mutations in NBAS, coding for a protein involved in Golgi-to-ER transport. NBAS deficiency causes several rare conditions ranging from isolated recurrent acute liver failure to a multisystem disorder mainly characterized by short stature, optic nerve atrophy and Pelger-Huët anomaly (SOPH). Since we subsequently verified Pelger-Huët anomaly in two of the patients the diagnosis SOPH syndrome was unequivocally proven. Our data show that SOPH syndrome can be regarded as a differential diagnosis for the progeroid forms of cutis laxa in early infancy and that possibly treatment of the hypogammaglobulinemia can be of high relevance for the prognosis.


Assuntos
Transtornos do Crescimento/diagnóstico , Proteínas de Neoplasias/genética , Doenças do Nervo Óptico/diagnóstico , Anomalia de Pelger-Huët/diagnóstico , Agamaglobulinemia/sangue , Agamaglobulinemia/fisiopatologia , Cútis Laxa/diagnóstico , Cútis Laxa/genética , Cútis Laxa/patologia , Diagnóstico Diferencial , Tecido Elástico/ultraestrutura , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Humanos , Lactente , Fígado/enzimologia , Fígado/patologia , Masculino , Doenças do Nervo Óptico/genética , Doenças do Nervo Óptico/patologia , Anomalia de Pelger-Huët/genética , Anomalia de Pelger-Huët/patologia , Progéria/diagnóstico , Progéria/genética , Pele/patologia , Síndrome , Sequenciamento Completo do Exoma , Adulto Jovem
8.
J Pediatr Endocrinol Metab ; 32(4): 415-419, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30893054

RESUMO

Background Monoallelic mutations of GHR have been described in idiopathic short stature (ISS), although the significance of these remain unclear. We report a case of ISS with novel monoallelic S219L mutation of GHR and discuss the possible significance of monoallelic GHR mutation in ISS. Case presentation The proband, a 13.9-year-old Japanese boy, had severe short stature (-3.8 standard deviation [SD]). Serum insulin-like growth factor (IGF)-I level and growth hormone (GH) secretion was normal. His parents were nonconsanguineous and had normal stature. Genetic analyses revealed a novel monoallelic missense variation in exon 7 of GHR (S219L). The proband's mother had the same variation. S219L might be the novel mutation judging from there being no registration of it as a single-nucleotide polymorphism (SNP) in any database, evolutional conservation of Ser219, in silico analyses, and computational molecular visualization analysis. Furthermore, a review of the literature showed that the median height of missense mutation carriers of GHR was relatively low. Conclusions We propose the possibility that monoallelic mutation of GHR increases the susceptibility to short stature.


Assuntos
Estatura/genética , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Hormônio do Crescimento Humano/genética , Mutação , Adolescente , Alelos , Humanos , Masculino , Prognóstico
9.
Arch Endocrinol Metab ; 63(1): 70-78, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30864634

RESUMO

Short stature is a common feature, and frequently remains without a specific diagnosis after conventional clinical and laboratorial evaluation. Longitudinal growth is mainly determined by genetic factors, and hundreds of common variants have been associated to height variability among healthy individuals. Although isolated short stature may be caused by the combination of variants, with a deleterious impact on the growth of individuals with polygenic inheritance, recent studies have pointed out some monogenic defects as the cause of the growth disorder observed in nonsyndromic children. The majority of these defects are in genes related to the growth plate cartilage and in the growth hormone (GH) - insulin-like growth factor 1 (IGF-1) axis. Affected patients usually present the mildest spectrum of some forms of skeletal dysplasia, or subtle abnormalities of laboratory tests, suggesting hormonal resistance or insensibility. The lack of specific characteristics, however, does not allow formulation of a definitive diagnosis without the use of broad genetic studies. Thus, molecular genetic studies including panels of genes or exome analysis will become essential in investigating and identifying the causes of isolated short stature in children, with a crucial impact on treatment and follow-up.


Assuntos
Estatura/genética , Variação Genética/genética , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/genética , Fator de Crescimento Insulin-Like I/genética , Humanos
11.
Mol Cell ; 73(3): 562-573.e3, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30595439

RESUMO

Across eukaryotes, disruption of DNA replication causes an S phase checkpoint response, which regulates multiple processes, including inhibition of replication initiation and fork stabilization. How these events are coordinated remains poorly understood. Here, we show that the replicative helicase component Cdc45 targets the checkpoint kinase Rad53 to distinct replication complexes in the budding yeast Saccharomyces cerevisiae. Rad53 binds to forkhead-associated (FHA) interaction motifs in an unstructured loop region of Cdc45, which is phosphorylated by Rad53 itself, and this interaction is necessary for the inhibition of origin firing through Sld3. Cdc45 also recruits Rad53 to stalled replication forks, which we demonstrate is important for the response to replication stress. Finally, we show that a Cdc45 mutation found in patients with Meier-Gorlin syndrome disrupts the functional interaction with Rad53 in yeast. Together, we present a single mechanism by which a checkpoint kinase targets replication initiation and elongation complexes, which may be relevant to human disease.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , Dano ao DNA , Reparo do DNA , Replicação do DNA , DNA Fúngico/biossíntese , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimologia , Proteínas de Ciclo Celular/genética , Quinase do Ponto de Checagem 2/genética , Microtia Congênita/enzimologia , Microtia Congênita/genética , DNA Fúngico/genética , Proteínas de Ligação a DNA/genética , Transtornos do Crescimento/enzimologia , Transtornos do Crescimento/genética , Humanos , Micrognatismo/enzimologia , Micrognatismo/genética , Mutação , Proteínas Nucleares/genética , Patela/anormalidades , Patela/enzimologia , Fosforilação , Ligação Proteica , Pontos de Checagem da Fase S do Ciclo Celular , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Proteínas de Saccharomyces cerevisiae/genética
12.
J Clin Immunol ; 39(1): 99-105, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30617623

RESUMO

DNA ligase IV (LIG4) syndrome is a rare autosomal recessive disorder, manifesting with variable immune deficiency, growth failure, predisposition to malignancy, and cellular sensitivity to ionizing radiation. The facial features are subtle and variable, as well. Herein, we described an 18-year-old boy, the first child of consanguineous parents who presented with Behçet's disease (BD)-like phenotype, developmental delay, and dysembryoplastic neuroepithelial tumor (DNET). Whole-exome sequencing revealed a homozygous p.Arg871His (c.2612G > A) mutation in LIG4. To date, 35 cases have been reported with LIG4 syndrome. Peripheral blood mononuclear cells of the patient displayed notable sensitivity to ionizing radiation. Flow cytometric annexin V-propidium iodide (PI) and eFluor670 proliferation assays showed accelerated radiation-induced apoptosis and diminished proliferation, respectively. To our knowledge, this is the first case presenting with a BD-like phenotype. This case provides further evidence that rare monogenic defects could be the underlying cause of atypical presentations of some well-described disorders. Moreover, this clinical report further expands the phenotypical spectrum of LIG4 deficiency.


Assuntos
Síndrome de Behçet/genética , DNA Ligase Dependente de ATP/genética , Mutação de Sentido Incorreto/genética , Adolescente , Anormalidades Craniofaciais/genética , Transtornos do Crescimento/genética , Homozigoto , Humanos , Síndromes de Imunodeficiência/genética , Leucócitos Mononucleares , Masculino , Fenótipo , Sequenciamento Completo do Exoma/métodos
13.
Arch Pediatr ; 26(2): 102-107, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30638765

RESUMO

BACKGROUND AND OBJECTIVES: Sanjad-Sakati syndrome (SSS; OMIM 241410) is a rare autosomal recessive disorder found almost exclusively in people of Arab origin. It is characterized by congenital hypoparathyroidism, severe prenatal and postnatal growth retardation, and distinct facial dysmorphism. The molecular pathology of this syndrome was shown to be due to a mutation in the tubulin-specific chaperone E (TBCE) gene in chromosomal area 1q42-q43. We aimed to detect and confirm the common mutation responsible for SSS in Tunisian patients and review the literature in order to create a set of clinical diagnostic criteria that might provide appropriate indications for molecular testing. METHODS: Three Tunisian patients with clinical feature of SSS were examined via direct Sanger sequencing of exon 3 of the TBCE gene. RESULTS: Mutation analysis of the TBCE gene revealed the common 12-bp (155-166del) deletion in three new patients, thus raising the number of reported SSS patients to 73. Reviewing the literature, we suggest a scoring system that assigns one point each for major criteria and one half point for minor criteria. INTERPRETATION AND CONCLUSIONS: SSS is an autosomal recessive disorder found in the Middle Eastern population with an estimated incidence of 1 per 40,000-100,000 live births in Saudi Arabia. Reviewing the literature on both its clinical and biochemical characteristics, we suggest for the first time, based on defined major and minor SSS criteria, a clinical scoring system for the diagnosis of SSS. On the one hand, an established scoring system will provide appropriate indications for molecular testing and, on the other hand, reviewed data on SSS will help delineate the phenotype and draw a distinction between differential diagnoses.


Assuntos
Anormalidades Múltiplas/diagnóstico , Transtornos do Crescimento/diagnóstico , Hipoparatireoidismo/diagnóstico , Deficiência Intelectual/diagnóstico , Chaperonas Moleculares/genética , Osteocondrodisplasias/diagnóstico , Convulsões/diagnóstico , Anormalidades Múltiplas/genética , Consenso , Feminino , Marcadores Genéticos , Transtornos do Crescimento/genética , Humanos , Hipoparatireoidismo/genética , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Osteocondrodisplasias/genética , Convulsões/genética , Deleção de Sequência , Tunísia
14.
Immunol Rev ; 287(1): 135-144, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565252

RESUMO

Dynamic changes in metabolism have long been understood as critical for both the initiation and maintenance of innate and adaptive immune responses. A number of recent advances have clarified details of how metabolic pathways can specifically affect cellular function in immune cells. Critical to this understanding is ongoing study of the congenital disorders of glycosylation and other genetic disorders of metabolism that lead to altered immune function in humans. While there are a number of immune phenotypes associated with metabolic derangements caused by single gene disorders, several genetic mutations have begun to link discrete alterations in metabolism and growth specifically with allergic disease. This subset of primary atopic disorders is of particular interest as they illuminate how hypomorphic mutations which allow for some residual function of mutated protein products permit the "abnormal" allergic response. This review will highlight how mutations altering sugar metabolism and mTOR activation place similar constraints on T lymphocyte metabolism to engender atopy, and how alterations in JAK/STAT signaling can impair growth and cellular metabolism while concomitantly promoting allergic diseases and reactions in humans.


Assuntos
Transtornos do Crescimento/genética , Mutação/genética , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR/genética , Animais , Humanos , Hipersensibilidade Imediata , Janus Quinases/metabolismo , Erros Inatos do Metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Açúcares/metabolismo , Serina-Treonina Quinases TOR/metabolismo
15.
Am J Med Genet C Semin Med Genet ; 178(4): 432-439, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30580482

RESUMO

Rhombencephalosynapsis (RES) is a unique cerebellar malformation characterized by fusion of the cerebellar hemispheres with partial or complete absence of a recognizable cerebellar vermis. Subsets of patients also have other brain malformations such as midbrain fusion with aqueductal stenosis, characteristic craniofacial features (prominent forehead, flat midface, hypertelorism, ear abnormalities), and somatic malformations (heart, kidney, spine, and limb defects). Similar to known genetic brain malformations, the RES cerebellar malformation is highly stereotyped, yet no genetic causes have been identified. Here, we outline our current understanding of the genetic basis for RES, discuss limitations, and outline future approaches to identifying the causes of this fascinating brain malformation.


Assuntos
Doenças Cerebelares/diagnóstico , Doenças Cerebelares/genética , Cerebelo/anormalidades , Transtornos do Crescimento/diagnóstico , Rombencéfalo/anormalidades , Transtornos do Crescimento/genética , Humanos , Rombencéfalo/patologia
16.
Am J Med Genet C Semin Med Genet ; 178(4): 387-397, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30580484

RESUMO

Dubowitz syndrome was described in 1965 as a recognizable syndrome characterized by microcephaly, short stature, eczema, mild developmental delays, and an increased risk of malignancy. Since its original description, there have been over 200 reported cases though no single gene has been identified to explain a significant proportion of affected individuals. Since the last definitive review of Dubowitz syndrome in 1996, there have been 63 individuals with a clinical, or suspected, diagnosis of Dubowitz syndrome reported in 51 publications. These individuals show a markedly wide spectrum with respect to growth, facial gestalt, psychomotor development, and risk of malignancy; genetic causes were identified in 33% (21/63). Seven individuals had deleterious copy number variants, in particular deletions at 14q32 and 17q24 were reported and showed overlap with the Dubowitz phenotype. Several cases were shown to have single gene disorders that included de novo or biallelic pathogenic variants in several genes including NSUN2 and LIG4 frequently identified by next-generation sequencing methods. It appears that the inability to identify a single gene responsible for Dubowitz syndrome reflects its extreme clinical and genetic heterogeneity. However, detailed phenotyping combined with careful grouping of subsets of unsolved cases and in conjunction with data-sharing will identify novel disease genes responsible for additional cases. In the interim, for those clinically diagnosed with a Dubowitz phenotype, we recommend assessment by a Medical Geneticist, a microarray and, if available, clinical or research based genome-wide sequencing. Management suggestions, including decisions regarding malignancy screening in select patients will be discussed.


Assuntos
Eczema/diagnóstico , Eczema/terapia , Heterogeneidade Genética , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/terapia , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/terapia , Microcefalia/diagnóstico , Microcefalia/terapia , Criança , Gerenciamento Clínico , Eczema/genética , Facies , Feminino , Transtornos do Crescimento/genética , Humanos , Deficiência Intelectual/genética , Masculino , Metanálise como Assunto , Microcefalia/genética , Fenótipo , Prognóstico
17.
Rev. clín. med. fam ; 11(3): 172-175, oct. 2018. ilus, graf
Artigo em Espanhol | IBECS | ID: ibc-176097

RESUMO

El crecimiento es un proceso multifactorial y complejo determinado genéticamente. En los últimos años se han descrito un número creciente de genes implicados en la etiología de la talla baja, uno de ellos es el gen SHOX (Short Stature Homeobox), localizado en los brazos cortos de los cromosomas X e Y, responsable del crecimiento longitudinal y cuya alteración (déficit) ha sido relacionada con la talla baja en el síndrome de Turner. En este artículo presentamos 3 casos con alteración en el gen SHOX, pertenecientes a una misma familia heterocigótica, sospechados en Atención Primaria


Growth is a multifactorial and complexprocess which is genetically determined. In recent years a growing number of genes involved in the etiology of short stature have been described, one of which is the SHOX gene (Short Stature Homeobox), located on the short arms of the X and Y chromosomes, responsible for longitudinal growth, and whose alteration (deficit) has been related to short stature in Turner syndrome. In this article, we present 3 cases with alteration in the SHOX gene, belonging to the same heterozygous family, suspected in Primary Care


Assuntos
Humanos , Masculino , Feminino , Adolescente , Pessoa de Meia-Idade , Transtornos do Crescimento/genética , Deficiências do Desenvolvimento/genética , Transtornos do Crescimento/diagnóstico por imagem , Marcadores Genéticos , Predisposição Genética para Doença , Atenção Primária à Saúde/métodos , Aconselhamento Genético , Deleção de Genes
18.
Medicine (Baltimore) ; 97(33): e11636, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30113454

RESUMO

INTRODUCTION: Cockayne syndrome (CS) is a rare multisystemic autosomal recessive disease. The primary manifestations of which are developmental delay, neurological impairment, abnormal skin sensitivity to sunlight and unique facial appearance as sunken eyes, large ears, and thin large nose. The disorders of the nucleotide excision repair system significantly are caused by mutations of Excision repair cross-complementing group 6 (ERCC6) and Excision repair cross-complementing group 8 (ERCC8) genes, and the ERCC6 gene mutations are present in approximately 65% of cases. CASE PRESENTATION: Here we described a girl in a consanguineous Jordanian family with abnormal facial appearance and postnatal growth delay. She was not able to gain weight. Her condition deteriorated progressively and she developed difficulty of swallowing even to water. The patient was diagnosed as CS based on her facial appearance and neurologic dysfunction. The patient was examined at 3 years old, and died at 4 years old. CONCLUSION: Genetic analysis and sequencing revealed homozygosity for a novel frame shift mutation c.2911_2915del5ins9 (p.Lys971TryfsX14) in the ERCC6. The mutation is predicted to delete 5 nucleotides and add 9 nucleotides with a premature termination, resulting in approximately 34% length reduction of the wild-type transcript. The multisystem malformations of CS are clinically heterogeneous. The frame shift mutation of ERCC6 found in this patient is a novel one, which caused postnatal growth failure and early death. Our findings indicate truncated mutation in CS lead to more severe CS phenotype and add to the genotype-phenotype correlations in CS.


Assuntos
Síndrome de Cockayne/genética , DNA Helicases/genética , Enzimas Reparadoras do DNA/genética , Deficiências do Desenvolvimento/diagnóstico , Mutação da Fase de Leitura/genética , Mutação , Proteínas de Ligação a Poli-ADP-Ribose/genética , Pré-Escolar , Síndrome de Cockayne/complicações , Síndrome de Cockayne/mortalidade , Consanguinidade , Reparo do DNA/genética , Deficiências do Desenvolvimento/etiologia , Evolução Fatal , Feminino , Estudos de Associação Genética/métodos , Transtornos do Crescimento/genética , Crescimento e Desenvolvimento/genética , Humanos , Jordânia/epidemiologia , Fenótipo
19.
Medicine (Baltimore) ; 97(32): e11328, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30095610

RESUMO

RATIONALE: Supernumerary teeth are those that teeth in excess number than the normal count. It is usually associated with genetic syndromes when present in more numbers. Several causal genes, such as APC, NHS, TRPS1, EVC and RUNX2, have been identified. However, etiology of supernumerary teeth remains largely unclear. PATIENT CONCERNS: A family with the clinical diagnosis of supernumerary teeth, short stature and craniofacial dysplasia was examined. DIAGNOSES: Molecular genetic analysis found that mutation occurred in the RUNX2 gene. On the basis of this finding and clinical manifestations, the final diagnosis of cleidocranial dysplasia was made. INTERVENTIONS: Whole exome sequencing (WES) of DNA samples was performed to identify the disease-causing mutation, including the affected child and mother as well as the healthy father. OUTCOMES: A novel mutation of RUNX2 (c.473C>A; p.A158E) was identified in both patients, but not in normal family member and in-house database containing 3,000 Chinese Han individuals WES. This mutation was further confirmed by Sanger sequencing and predicted to be deleterious by several commonly used algorithms, including SIFT, PPT-2, MutationTaster and Proven. Furthermore, phenotype-genotype correlation analyses of all published 239 cases with different mutations in RUNX2 revealed significant association of supernumerary teeth and facial dysplasia with the Runt domain of the encoded protein. LESSONS: This is the first WES study to identify genetic cause in Chinese patients with a novel RUNX2 mutation. Our findings expanded the mutation spectrum and clinical features of the disease and facilitated clinic diagnosis and genetic counseling.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Anormalidades Craniofaciais/genética , Mutação de Sentido Incorreto , Dente Supranumerário/genética , Adolescente , Feminino , Transtornos do Crescimento/genética , Humanos , Pessoa de Meia-Idade , Linhagem , Sequenciamento Completo do Exoma
20.
Eur J Endocrinol ; 179(3): 181-190, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29973376

RESUMO

OBJECTIVE: Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development. METHODS: Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France. RESULTS: Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 ± 7.6 cm, i.e. -2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% (n = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels). CONCLUSION: This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies.


Assuntos
Cromossomos Humanos X , Transtorno 46,XY do Desenvolvimento Sexual/patologia , Genitália/anormalidades , Mosaicismo , Aberrações dos Cromossomos Sexuais , Transtornos dos Cromossomos Sexuais/patologia , Adulto , Azoospermia/diagnóstico , Azoospermia/genética , Estatura , Criança , Feminino , Seguimentos , França , Genitália/crescimento & desenvolvimento , Genitália/patologia , Transtornos do Crescimento/genética , Humanos , Recém-Nascido , Cariotipagem , Estudos Longitudinais , Masculino , Monossomia , Fenótipo , Gravidez , Diagnóstico Pré-Natal , Puberdade , Estudos Retrospectivos
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