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1.
PLoS Genet ; 15(4): e1008088, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31034465

RESUMO

PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. In particular, the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe's syndrome, which is caused by mutations in the PI-5-phosphatase OCRL, highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Catarata/genética , Transtornos da Motilidade Ciliar/genética , Nanismo/genética , Mutação , Fosfatidilinositol 3-Quinases/genética , Adolescente , Adulto , Criança , Consanguinidade , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Linhagem , Fenótipo , Adulto Jovem
2.
Orthop Clin North Am ; 50(2): 193-209, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850078

RESUMO

Osteogenesis imperfecta is a genetically and phenotypically heterogeneous disorder related to a defect or deficiency in the production of type I collagen. It is characterized by brittle bones, fractures, spine and extremity deformity, and a host of extraskeletal manifestations. Type I collagen is present in bone, tendons, ligaments, skin, dentin, and the sclera of the eye and other connective tissues. Osteogenesis imperfecta includes a multitude of disease manifestations that may be present at birth or develop over time and vary depending on the severity of the disease. This article describes the disease presentation and management considerations from a pediatric orthopedic perspective.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Deformidades Congênitas dos Membros/diagnóstico , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/genética , Adolescente , Doenças do Desenvolvimento Ósseo/patologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Cálcio/administração & dosagem , Cálcio/uso terapêutico , Criança , Pré-Escolar , Difosfonatos/administração & dosagem , Difosfonatos/uso terapêutico , Exercício/fisiologia , Feminino , Órtoses do Pé/normas , Fraturas Ósseas/complicações , Fraturas Ósseas/terapia , Humanos , Lactente , Comunicação Interdisciplinar , Deformidades Congênitas dos Membros/etiologia , Deformidades Congênitas dos Membros/cirurgia , Deformidades Congênitas dos Membros/terapia , Masculino , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/patologia , Escoliose/patologia , Escoliose/cirurgia , Coluna Vertebral/anormalidades , Coluna Vertebral/patologia , Vitamina D/uso terapêutico
3.
Mol Genet Genomics ; 294(3): 773-787, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30887145

RESUMO

The latent transforming growth factor-beta-binding protein 3 (LTBP3), encoding extracellular matrix proteins, plays a role in skeletal formation. Mutations in LTBP3 have been associated with various types of skeletal dysplasia. We aimed to characterize clinical and molecular features of more patients with mutations in the gene, which may help suggest genotype-phenotype correlation. The first two East Asian patients with short stature, heart defects, and orodental anomalies having LTBP3 mutations were identified. Whole exome and Sanger sequencing revealed that the one with a novel heterozygous missense (c.2017G>T, p.Gly673Cys) mutation in LTBP3 had clinical features consistent with acromicric dysplasia (ACMICD). The variant was located in the highly conserved EGF-like calcium-binding domain adjacent to the single reported LTBP3 variant associated with ACMICD. This finding supports that LTBP3 is a disease gene for ACMICD. Another patient with a novel homozygous splice site acceptor (c.1721-2A>G) mutation in LTBP3 was affected with dental anomalies and short stature (DASS). Previously undescribed orodental features included multiple unerupted teeth, high-arched palate, and microstomia found in our patient with ACMICD, and extensive dental infection, condensing osteitis, and deviated alveolar bone formation in our patient with DASS. Our results and comprehensive reviews suggest a genotype-phenotype correlation: biallelic loss-of-function mutations cause DASS, monoallelic missense gain-of-function mutations in the EGF-like domain cause ACMICD, and monoallelic missense gain-of-function mutations with more drastic effects on the protein functions cause geleophysic dysplasia (GPHYSD3). In summary, we expand the phenotypic and genotypic spectra of LTBP3-related disorders, support that LTBP3 is a disease gene for ACMICD, and propose the genotype-phenotype correlation of LTBP3 mutations.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Estudos de Associação Genética/métodos , Proteínas de Ligação a TGF-beta Latente/genética , Deformidades Congênitas dos Membros/genética , Mutação , Anormalidades Dentárias/genética , Adolescente , Sequência de Aminoácidos , Criança , Nanismo/genética , Feminino , Humanos , Masculino , Linhagem , Homologia de Sequência de Aminoácidos , Adulto Jovem
4.
Clin Calcium ; 29(3): 323-328, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-30814377

RESUMO

Identification of responsible genes for skeletal dysplasias evidences their critical roles in the skeletal development and maintenance. Mutations in the genes encoding the components of Wnt canonical pathway, which include WNT1, LRP5, LRP4, SOST and WTX, cause the disorders characterized by abnormal in bone mass. On the other hand, mutations in the genes for the components of Wnt non-canonical pathway such as WNT5A, ROR2, DVL1 and DVL3 are associated with dysmorphic skeletal disorders which manifest short limbs and facial anomalies. Thus, both canonical and non-canonical pathways of Wnt signaling play substantial roles in the human skeletons, and it is suggested that the former mainly controls bone mass while the latter regulates skeletal morphogenesis.


Assuntos
Doenças do Desenvolvimento Ósseo/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , Doenças do Desenvolvimento Ósseo/genética , Humanos , Mutação , Proteínas Wnt/genética
5.
Nat Med ; 25(4): 583-590, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30804514

RESUMO

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders1-5, but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia. Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice6. This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects. In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects. Furthermore, the mutant miR-140-5p seed competes with the conserved RNA-binding protein Ybx1 for overlapping binding sites. This finding may explain the potent target repression and robust in vivo effect by this mutant miRNA even in the absence of evolutionary selection of miRNA-target RNA interactions, which contributes to the strong regulatory effects of conserved miRNAs7,8. Our study presents the first case of a pathogenic gain-of-function miRNA mutation and provides molecular insight into neomorphic actions of emerging and/or mutant miRNAs.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Mutação com Ganho de Função/genética , MicroRNAs/genética , Animais , Sequência de Bases , Condrócitos/metabolismo , Feminino , Homozigoto , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , MicroRNAs/metabolismo , Linhagem , Fenótipo , Transcriptoma/genética
6.
Genes Brain Behav ; 18(4): e12553, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30786142

RESUMO

KBG syndrome is a neurodevelopmental disorder, caused by dominant mutations in ANKRD11, that is characterized by developmental delay/intellectual disability, mild craniofacial dysmorphisms, and short stature. Behavior and cognition have hardly been studied, but anecdotal evidence suggests higher frequencies of ADHD-symptoms and social-emotional impairments. In this study, the behavioral and cognitive profile of KBG syndrome will be investigated in order to examine if and how cognitive deficits contribute to behavioral difficulties. A total of 18 patients with KBG syndrome and a control group consisting of 17 patients with other genetic disorders with comparable intelligence levels, completed neuropsychological assessment. Age-appropriate tasks were selected, covering overall intelligence, attention, memory, executive functioning, social cognition and visuoconstruction. Results were compared using Cohen's d effect sizes. As to behavior, fewer difficulties in social functioning and slightly more attentional problems, hyperactivity, oppositional defiant behavior and conduct problems were found in the KBG syndrome group. Regarding cognitive functioning, inspection of the observed differences shows that patients with KBG syndrome showed lower scores on sustained attention, cognitive flexibility, and visuoconstruction. In contrast, the KBG syndrome group demonstrated higher scores on visual memory, social cognition and emotion recognition. The cognitive profile of KBG syndrome in this sample indicates problems in attention and executive functioning that may underlie the behavior profile which primarily comprises impulsive behavior. Contrary to expectations based on previous (case) reports, no deficits were found in social cognitive functioning. These findings are important for counseling purposes, for tailored education planning, and for the development of personalized intervention.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Cognição , Deficiência Intelectual/fisiopatologia , Fenótipo , Anormalidades Dentárias/fisiopatologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/psicologia , Adolescente , Adulto , Idoso , Atenção , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/psicologia , Criança , Função Executiva , Facies , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Inteligência , Masculino , Memória , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Comportamento Social , Anormalidades Dentárias/genética , Anormalidades Dentárias/psicologia , Percepção Visual
7.
Mol Genet Genomic Med ; 7(4): e00567, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30722102

RESUMO

BACKGROUND: Follistatin-like 1 (Fstl1) is a glycoprotein expressed throughout embryonic development. Homozygous loss of Fstl1 in mice results in skeletal and respiratory defects, leading to neonatal death due to a collapse of the trachea. Furthermore, Fstl1 conditional deletion from the endocardial/endothelial lineage results in postnatal death due to heart failure and profound atrioventricular valve defects. Here, we investigated patients with phenotypes similar to the phenotypes observed in the transgenic mice, for variants in FSTL1. METHODS: In total, 69 genetically unresolved patients were selected with the following phenotypes: campomelic dysplasia (12), small patella syndrome (2), BILU (1), and congenital heart disease patients (54), of which 16 also had kyphoscoliosis, and 38 had valve abnormalities as their main diagnosis. Using qPCR, none of 69 patients showed copy number variations in FSTL1. The entire gene body, including microRNA-198 and three validated microRNA-binding sites, were analyzed using Sanger sequencing. RESULTS: No variants were found in the coding region. However, 8 intronic variants were identified that differed significantly in their minor allele frequency compared to controls. Variant rs2272515 was found to significantly correlate (p < 0.05) with kyphoscoliosis. CONCLUSION: We conclude that pathogenic variants in FSTL1 are unlikely to be responsible for skeletal or atrioventricular valve anomalies in humans.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Displasia Campomélica/genética , Variações do Número de Cópias de DNA , Proteínas Relacionadas à Folistatina/genética , Doenças das Valvas Cardíacas/genética , Quadril/anormalidades , Ísquio/anormalidades , Cifose/genética , Patela/anormalidades , Polimorfismo de Nucleotídeo Único , Doenças do Desenvolvimento Ósseo/patologia , Displasia Campomélica/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Doenças das Valvas Cardíacas/patologia , Quadril/patologia , Humanos , Ísquio/patologia , Cifose/patologia , Patela/patologia
8.
Gene ; 697: 48-56, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30790652

RESUMO

BACKGROUND: Autosomal recessive disorder is closely correlated with congenital fetal malformation. The mutation of WDR35 may lead to short rib-polydactyly syndrome (SRP), asphyxiating thoracic dystrophy (ATD, Jeune syndrome) and Ellis van Creveld syndrome. The purpose of this study is to investigate the role of WDR35 in fetal anomaly. RESULTS: The fetuses presented malformation with abnormal head shape, cardiac dilatation, pericardial effusion, and non-displayed left pulmonary artery and left lung. After the detection of genomic DNA (gDNA) in amniotic fluid cells (AFC), chromosomal rearrangement was found in arr[hg19] 2p25.3p23.3. It was revealed through multiple PCR-DHPLC that MYCN, WDR35, LPIN1, ODC1, KLF11 and NBAS contained duplicated copy numbers in 2p25.3p23.3. AF-MSCs were mostly positive for CD44, CD105, negative for CD34 and CD14. Western Blot test showed that WDR35-encoded protein was decreased in the patients' AFC compared to that in normal pregnant women. In the patients' amniotic fluid-derived mesenchymal stem cells (AF-MSCs), WDR35 overexpression could repair cilia formation, and the overexpression of WDR35 or Gli2 could significantly enhance ALP activity and expressions of osteogenic differentiation marker genes, including RUNXE2, OCN, BSP and ALP. However, WDR35 silencing in C3H10T1/2 cells could remarkably inhibit cilia formation and osteogenic differentiation. This inhibitory effect could be attenuated by Gli2 overexpression. CONCLUSIONS: The results demonstrated that copy number variation (CNV) of WDR35 may lead to skeletal dysplasia and fetal anomaly, and that down-regulated WDR35 may damage the cilia formation and sequentially indirectly regulate Gli signal, which would eventually result in negative regulation of osteogenic differentiation.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Osteogênese/fisiologia , Proteínas/genética , Adulto , Líquido Amniótico/química , Líquido Amniótico/citologia , Animais , Doenças do Desenvolvimento Ósseo/metabolismo , Diferenciação Celular/fisiologia , Cílios/genética , Cílios/fisiologia , Variações do Número de Cópias de DNA , Feminino , Desenvolvimento Fetal/genética , Humanos , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C3H , Fenótipo , Polimorfismo de Nucleotídeo Único , Gravidez , Proteínas/metabolismo
9.
BMC Med Genet ; 20(1): 16, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642272

RESUMO

BACKGROUND: KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. CASE PRESENTATION: Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. CONCLUSIONS: This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Epilepsia Generalizada/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Mutação , Fenótipo , Proteínas Repressoras/genética , Convulsões Febris/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Alelos , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/etiologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Brasil , Eletroencefalografia , Epilepsia Generalizada/fisiopatologia , Facies , Feminino , Loci Gênicos , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/etiologia , Deficiência Intelectual/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Linhagem , Convulsões Febris/fisiopatologia , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/etiologia , Anormalidades Dentárias/fisiopatologia , Sequenciamento Completo do Exoma
10.
Proteomics Clin Appl ; 13(2): e1800135, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30548811

RESUMO

BACKGROUND: Progeria-like syndromes offer a unique insight into aging. Here the case of a boy affected with mandibuloacral dysplasia and compound heterozygous mutations in ZMPSTE24 is presented. METHODS: Capillary electrophoresis-mass spectroscopy is used for proteome analysis to analyze peptides previously found to be differentially regulated in chronic kidney disease (273 peptides defining the CKD273 classifier), coronary artery disease (238 peptides defining the CAD238 classifier), and aging (116 peptides defining the AGE116 classifier). RESULTS: No evidence of renal disease is identified. Although the boy has no overt cardiovascular disease other than a raised carotid intima media thickness relative to his age, a proteomic classifier for the diagnosis of coronary artery disease is mildly raised. The biological age based on the proteomic AGE116 classifier is 24 years compared to the chronological ages of 5 and 10 years. In contrast, a control group of healthy children has a significantly lower (p < 0.0001) calculated mean age of 13. CONCLUSION: Urinary proteomic analysis is effective in confirming advanced biological age and to identify early evidence of renal or cardiovascular damage. This case highlights the value of proteomic approaches in aging research and may represent a method for non-invasive monitoring of the effects of early aging.


Assuntos
Envelhecimento/genética , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Heterozigoto , Proteínas de Membrana/genética , Metaloendopeptidases/genética , Mutação , Proteômica , Criança , Pré-Escolar , Humanos
11.
Hum Mol Genet ; 28(7): 1183-1198, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30544148

RESUMO

Natriuretic peptide receptor B (NPRB) produces cyclic guanosine monophosphate (cGMP) when bound by C-type natriuretic peptide (CNP). Activating mutations in NPRB cause a skeletal overgrowth disorder, which has been named epiphyseal chondrodysplasia, Miura type (ECDM; OMIM #615923). Here we explored the cellular and molecular mechanisms for the skeletal overgrowth in ECDM using a mouse model in which an activating mutant NPRB is specifically expressed in chondrocytes. The mutant mice (NPRB[p.V883M]-Tg) exhibited postnatal skeletal overgrowth and increased cGMP in cartilage. Both endogenous and transgene-derived NPRB proteins were localized at the plasma membrane of hypertrophic chondrocytes. The hypertrophic zone of growth plate was thickened in NPRB[p.V883M]-Tg. An in vivo BrdU-labeling assay suggested that some of the hypertrophic chondrocytes in NPRB[p.V883M]-Tg mice continued to proliferate, although wild-type (WT) chondrocytes stopped proliferating after they became hypertrophic. In vitro cell studies revealed that NPRB activation increased the phosphorylation of cyclic AMP-responsive element binding protein (CREB) and expression of cyclin D1 in matured chondrocytes. Treatment with cell-permeable cGMP also enhanced the CREB phosphorylation. Inhibition of cyclic adenosine monophosphate (cAMP)/protein kinase A pathway had no effects on the CREB phosphorylation induced by NPRB activation. In immunostaining of the growth plates for the proliferation marker Ki67, phosphorylated CREB and cyclin D1, most signals were similarly observed in the proliferating zone in both genotypes, but some cells in the hypertrophic zone of NPRB[p.V883M]-Tg were also positively stained. These results suggest that NPRB activation evokes its signal in hypertrophic chondrocytes to induce CREB phosphorylation and make them continue to proliferate, leading to the skeletal overgrowth in ECDM.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Receptores do Fator Natriurético Atrial/genética , Animais , Doenças do Desenvolvimento Ósseo/fisiopatologia , Cartilagem/crescimento & desenvolvimento , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Condrócitos/fisiologia , Condrogênese/genética , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Mutação com Ganho de Função/genética , Lâmina de Crescimento/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosforilação
13.
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
15.
PLoS One ; 13(3): e0194812, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29566041

RESUMO

We have previously investigated the physiological role of C-type natriuretic peptide (CNP) on endochondral bone growth, mainly with mutant mouse models deficient in CNP, and reported that CNP is indispensable for physiological endochondral bone growth in mice. However, the survival rate of CNP knockout (KO) mice fell to as low as about 70% until 10 weeks after birth, and we could not sufficiently analyze the phenotype at the adult stage. Herein, we generated CNP KO rats by using zinc-finger nuclease-mediated genome editing technology. We established two lines of mutant rats completely deficient in CNP (CNP KO rats) that exhibited a phenotype identical to that observed in mice deficient in CNP, namely, a short stature with severely impaired endochondral bone growth. Histological analysis revealed that the width of the growth plate, especially that of the hypertrophic chondrocyte layer, was markedly lower and the proliferation of growth plate chondrocytes tended to be reduced in CNP KO rats. Notably, CNP KO rats did not have malocclusions and survived for over one year after birth. At 33 weeks of age, CNP KO rats persisted significantly shorter than wild-type rats, with closed growth plates of the femur in all samples, which were not observed in wild-type rats. Histologically, CNP deficiency affected only bones among all body tissues studied. Thus, CNP KO rats survive over one year, and exhibit a deficit in endochondral bone growth and growth retardation throughout life.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Peptídeo Natriurético Tipo C/genética , Animais , Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/mortalidade , Doenças do Desenvolvimento Ósseo/patologia , Nanismo/genética , Nanismo/patologia , Feminino , Deleção de Genes , Técnicas de Inativação de Genes , Lâmina de Crescimento/patologia , Osteogênese/genética , Ratos , Ratos Endogâmicos F344 , Ratos Transgênicos
16.
Eur J Med Genet ; 61(4): 219-224, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29191498

RESUMO

Acromelic dysplasia is a heterogeneous group of rare skeletal dysplasias characterized by distal limb shortening. Weill-Marchesani syndrome (WMS), Geleophysic dysplasia (GD) and Acromicric dysplasia (AD) are clinically distinct entities within this group of disorders and are characterized by short stature, short hands, stiff joints, skin thickening, facial anomalies, normal intelligence and skeletal abnormalities. Mutations of the Fibrillin-1 (FBN1) gene have been reported to cause AD, GD and related phenotypes. We reported three families with acromelic short stature. FBN1 analysis showed that all affected individuals carry a heterozygous missense mutation c.5284G > A (p.Gly1762Ser) in exon 42 of the FBN1 gene. This mutation was previously reported to be associated with GD. We reviewed the literature and compared the clinical features of the patients with FBN1 mutations to those with A Distintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2) mutations. We found that tip-toeing gait, long flat philtrum and thin upper upper lip were more consistently found in GD patients with ADAMTSL2 mutations than in those with FBN1 mutations. The results have shed some light on the phenotype-genotype correlation in this group of skeletal disorders. A large scale study involving multidisciplinary collaboration would be needed to consolidate our findings.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Fibrilina-1/genética , Deformidades Congênitas dos Membros/genética , Fenótipo , Síndrome de Weill-Marchesani/genética , Proteínas ADAMTS/genética , Doenças do Desenvolvimento Ósseo/patologia , Criança , Pré-Escolar , Feminino , Genótipo , Heterozigoto , Humanos , Deformidades Congênitas dos Membros/patologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Síndrome de Weill-Marchesani/patologia
17.
Orphanet J Rare Dis ; 12(1): 183, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29258554

RESUMO

CLINICAL DESCRIPTION: KBG syndrome is characterized by macrodontia of upper central incisors, distinctive craniofacial features such as triangular face, prominent nasal bridge, thin upper lip and synophrys; skeletal findings including short stature, delayed bone age, and costovertebral anomalies; and developmental delay/intellectual disability sometimes associated with seizures and EEG abnormalities. The condition was named KBG syndrome after the initials of the last names of three original families reported in 1975. EPIDEMIOLOGY: The prevalence of KBG syndrome is not established. There are over 100 patients reported in the literature. It is likely that KBG syndrome is underreported due to incomplete recognition and very mild presentations of the disorder in some individuals. KBG syndrome is typically milder in females. ETIOLOGY: Causative variants in ANKRD11 have been identified in affected individuals. The vast majority of identified variants are loss of function, which include nonsense and frameshift variants and larger deletions at 16q24.3. Haploinsufficiency appears to be the mechanism of pathogenicity. GENETIC COUNSELING: Familial and de novo cases have been reported. Causative de novo variants occur approximately one third of the time. Transmission follows an autosomal dominant pattern. The syndrome displays inter- and intra-familial variability.


Assuntos
Anormalidades Múltiplas/metabolismo , Doenças do Desenvolvimento Ósseo/metabolismo , Deficiência Intelectual/metabolismo , Anormalidades Dentárias/metabolismo , Anormalidades Múltiplas/genética , Animais , Doenças do Desenvolvimento Ósseo/genética , Deleção Cromossômica , Hibridização Genômica Comparativa , Facies , Feminino , Haploinsuficiência/genética , Haploinsuficiência/fisiologia , Humanos , Deficiência Intelectual/genética , Masculino , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Convulsões/genética , Convulsões/metabolismo , Anormalidades Dentárias/genética
18.
Int J Pediatr Otorhinolaryngol ; 103: 109-112, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29224748

RESUMO

KBG syndrome is a rare genetic disorder, due to a mutation of ANKRD11, characterized by specific craniofacial dysmorphism, short stature and macrodontia of upper central incisors, intellectual disability and skeletal anomalies. We report a de novo mutation of ANKRD11 gene in a 7-years old girl, affected by KBG syndrome with bilateral conductive hearing loss. The aim of this article was to review the audiological findings of this syndrome.


Assuntos
Anormalidades Múltiplas/diagnóstico , Doenças do Desenvolvimento Ósseo/diagnóstico , Perda Auditiva Condutiva/etiologia , Deficiência Intelectual/diagnóstico , Proteínas Repressoras/genética , Anormalidades Dentárias/diagnóstico , Anormalidades Múltiplas/genética , Audiometria , Doenças do Desenvolvimento Ósseo/complicações , Doenças do Desenvolvimento Ósseo/genética , Criança , Facies , Feminino , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Mutação , Fenótipo , Anormalidades Dentárias/complicações , Anormalidades Dentárias/genética
19.
Am J Hum Genet ; 101(5): 815-823, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100092

RESUMO

Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.


Assuntos
Fibronectinas/genética , Fraturas Ósseas/genética , Mutação/genética , Osteocondrodisplasias/genética , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/genética , Osso e Ossos/patologia , Cartilagem/patologia , Criança , Pré-Escolar , Exoma/genética , Feminino , Humanos , Masculino , Fenótipo , Escoliose/genética
20.
Am J Hum Genet ; 101(5): 844-855, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29100094

RESUMO

A series of simplex cases have been reported under various diagnoses sharing early aging, especially evident in congenitally decreased subcutaneous fat tissue and sparse hair, bone dysplasia of the skull and fingers, a distinctive facial gestalt, and prenatal and postnatal growth retardation. For historical reasons, we suggest naming the entity Fontaine syndrome. Exome sequencing of four unrelated affected individuals showed that all carried the de novo missense variant c.649C>T (p.Arg217Cys) or c.650G>A (p.Arg217His) in SLC25A24, a solute carrier 25 family member coding for calcium-binding mitochondrial carrier protein (SCaMC-1, also known as SLC25A24). SLC25A24 allows an electro-neutral and reversible exchange of ATP-Mg and phosphate between the cytosol and mitochondria, which is required for maintaining optimal adenine nucleotide levels in the mitochondrial matrix. Molecular dynamic simulation studies predict that p.Arg217Cys and p.Arg217His narrow the substrate cavity of the protein and disrupt transporter dynamics. SLC25A24-mutant fibroblasts and cells expressing p.Arg217Cys or p.Arg217His variants showed altered mitochondrial morphology, a decreased proliferation rate, increased mitochondrial membrane potential, and decreased ATP-linked mitochondrial oxygen consumption. The results suggest that the SLC25A24 mutations lead to impaired mitochondrial ATP synthesis and cause hyperpolarization and increased proton leak in association with an impaired energy metabolism. Our findings identify SLC25A24 mutations affecting codon 217 as the underlying genetic cause of human progeroid Fontaine syndrome.


Assuntos
Envelhecimento/genética , Antiporters/genética , Doenças do Desenvolvimento Ósseo/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas Mitocondriais/genética , Mutação/genética , Adenina/metabolismo , Trifosfato de Adenosina/metabolismo , Citosol/metabolismo , Feminino , Morte Fetal , Fibroblastos/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Potencial da Membrana Mitocondrial/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Simulação de Dinâmica Molecular , Oxigênio/metabolismo , Fosfatos/metabolismo , Síndrome
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