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1.
Genet Med ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31267042

RESUMO

In the Acknowledgements section of the paper the authors neglected to mention that the study was supported by a grant from the National Human Genome Research Institute (NHGRI) UM1HG007301 (S.H., M.L.T.). In addition, the award of MD was associated with the authors Michelle L. Thompson and Susan Hiatt instead of PhD. The PDF and HTML versions of the Article have been modified accordingly.

2.
Curr Opin Pediatr ; 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31361679

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to outline the current understanding of the molecular mechanisms and natural history of osteogenesis imperfecta, and to describe the development of new treatments for this disorder. RECENT FINDINGS: The introduction of next-generation sequencing technology has led to better understanding of the genetic cause of osteogenesis imperfecta and enabled cost-effective and timely diagnosis via expanded gene panels and exome or genome sequencing. Clinically, despite genetic heterogeneity, different forms of osteogenesis imperfecta share similar features that include connective tissue and systemic manifestations in addition to bone fragility. Thus, the goals of treatment in osteogenesis imperfecta extend beyond decreasing the risk of fracture, to include the maximization of growth and mobility, and the management of extraskeletal complications. The standard of care in pediatric patients is bisphosphonates therapy. Ongoing preclinical studies in osteogenesis imperfecta mouse models and clinical studies in individuals with osteogenesis imperfecta have been instrumental in the development of new and targeted therapeutic approaches, such as sclerostin inhibition and transforming growth factor-ß inhibition. SUMMARY: Osteogenesis imperfecta is a skeletal dysplasia characterized by bone fragility and extraskeletal manifestations. Better understanding of the mechanisms of osteogenesis imperfecta will enable the development of much needed targeted therapies to improve the outcome in affected individuals.

3.
Genet Med ; 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31155615

RESUMO

PURPOSE: Mediator is a multiprotein complex that allows the transfer of genetic information from DNA binding proteins to the RNA polymerase II during transcription initiation. MED12L is a subunit of the kinase module, which is one of the four subcomplexes of the mediator complex. Other subunits of the kinase module have been already implicated in intellectual disability, namely MED12, MED13L, MED13, and CDK19. METHODS: We describe an international cohort of seven affected individuals harboring variants involving MED12L identified by array CGH, exome or genome sequencing. RESULTS: All affected individuals presented with intellectual disability and/or developmental delay, including speech impairment. Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features. Three individuals had a MED12L deletion or duplication. The other four individuals harbored single-nucleotide variants (one nonsense, one frameshift, and two splicing variants). Functional analysis confirmed a moderate and significant alteration of RNA synthesis in two individuals. CONCLUSION: Overall data suggest that MED12L haploinsufficiency is responsible for intellectual disability and transcriptional defect. Our findings confirm that the integrity of this kinase module is a critical factor for neurological development.

4.
EMBO J ; 37(23)2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30420557

RESUMO

A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell degeneration (pcd) mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation. The human disease mainly affected the cerebellum, spinal motor neurons, and peripheral nerves. We also demonstrate previously unrecognized peripheral nerve and spinal motor neuron degeneration in pcd mice, which thus recapitulated key features of the human disease. Our findings link human neurodegeneration to tubulin polyglutamylation, entailing this post-translational modification as a potential target for drug development for neurodegenerative disorders.

5.
Am J Hum Genet ; 103(1): 154-162, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29961569

RESUMO

TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development.

6.
Mitochondrion ; 2018 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-29307858

RESUMO

Elevations of specific acylcarnitines in blood reflect carboxylase deficiencies, and have utility in newborn screening for life-threatening organic acidemias and other inherited metabolic diseases. In this report, we describe a newly-identified association of biochemical features of multiple carboxylase deficiency in individuals harboring mitochondrial DNA (mtDNA) mutations in MT-ATP6 and in whom organic acidemias and multiple carboxylase deficiencies were excluded. Using retrospective chart review, we identified eleven individuals with abnormally elevated propionylcarnitine (C3) or hydroxyisovalerylcarnitine (C5OH) with mutations in MT-ATP6, most commonly m.8993T>G in high heteroplasmy or homoplasmy. Most patients were ascertained on newborn screening; most had normal enzymatic or molecular genetic testing to exclude biotinidase and holocarboxylase synthetase deficiencies. MT-ATP6 is associated with some cases of Leigh disease; clinical outcomes in our cohort ranged from death from neurodegenerative disease in early childhood to clinically and developmentally normal after several years of follow-up. These cases expand the biochemical phenotype associated with MT-ATP6 mutations, especially m.8993T>G, to include acylcarnitine abnormalities mimicking carboxylase deficiency states. Clinicians should be aware of this association and its implications for newborn screening, and consider mtDNA sequencing in patients exhibiting similar acylcarnitine abnormalities that are biotin-unresponsive and in whom other enzymatic deficiencies have been excluded.

7.
Genome Med ; 9(1): 83, 2017 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-28934986

RESUMO

BACKGROUND: Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery. METHODS: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association. RESULTS: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses. CONCLUSIONS: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.


Assuntos
Variações do Número de Cópias de DNA , Éxons , Doenças Genéticas Inatas , Estudos de Coortes , Genoma Humano , Proteínas de Homeodomínio/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Serina-Treonina Quinases/genética , Estudos Retrospectivos , Fatores de Transcrição/genética , Sequenciamento Completo do Genoma
8.
Am J Med Genet A ; 173(10): 2789-2794, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28815944

RESUMO

Nemaline myopathy is a rare inherited disorder characterized by weakness, hypotonia, and depressed deep tendon reflexes. It is clinically and genetically heterogeneous, with the most severe phenotype presenting as perinatal akinesia, severe muscle weakness, feeding difficulties and respiratory failure, leading to early mortality. Pathogenic variants in 12 genes, encoding components of the sarcomere or factors related to myogenesis, have been reported in patients affected with the disorder. Here, we describe an early, lethal presentation of decreased fetal movements, hypotonia, muscle weakness, and neonatal respiratory failure requiring ventilator support in three siblings from a consanguineous family. All exhibited perinatal fractures, and thus, a skeletal dysplasia was considered as possibly contributing to the phenotype. However, whole exome sequencing revealed a homozygous, loss-of-function pathogenic variant in LMOD3, which has recently been associated with nemaline myopathy and, in a subset of patients, perinatal fractures. This case demonstrates the importance of considering congenital neuromuscular disorders in the differential diagnosis of perinatal fractures.


Assuntos
Fraturas Ósseas/patologia , Proteínas Musculares/genética , Mutação , Miopatias Congênitas Estruturais/patologia , Feminino , Fraturas Ósseas/complicações , Fraturas Ósseas/genética , Homozigoto , Humanos , Recém-Nascido , Masculino , Miopatias Congênitas Estruturais/complicações , Miopatias Congênitas Estruturais/genética , Linhagem
9.
Mol Genet Metab ; 122(1-2): 60-66, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28693988

RESUMO

INTRODUCTION: Cobalamin C disease is a multisystemic disease with variable manifestations and age of onset. Genotype-phenotype correlations are well-recognized in this disorder. Here, we present a large cohort of individuals with cobalamin C disease, several of whom are heterozygous for the c.482G>A pathogenic variant (p.Arg161Gln). We compared clinical characteristics of individuals with this pathogenic variant to those who do not have this variant. To our knowledge, this study represents the largest single cohort of individuals with the c.482G>A (p.Arg161Gln) pathogenic variant. METHODS: A retrospective chart review of 27 individuals from 21 families with cobalamin C disease who are followed at our facility was conducted. RESULTS: 13 individuals (48%) are compound heterozygous with the c.482G>A (p.Arg161Gln) on one allele and a second pathogenic variant on the other allele. Individuals with the c.482G>A (p.Arg161Gln) pathogenic variant had later onset of symptoms and easier metabolic control. Moreover, they had milder biochemical abnormalities at presentation which likely contributed to the observation that 4 individuals (31%) in this group were missed by newborn screening. CONCLUSION: The c.482G>A (p.Arg161Gln) pathogenic variant is associated with milder disease. These individuals may not receive a timely diagnosis as they may not be identified on newborn screening or because of unrecognized, late onset symptoms. Despite the milder presentation, significant complications can occur, especially if treatment is delayed.


Assuntos
Gerenciamento Clínico , Variação Genética , Homocistinúria/genética , Deficiência de Vitamina B 12/congênito , Adolescente , Adulto , Alelos , Proteínas de Transporte/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Estudos de Associação Genética , Genótipo , Heterozigoto , Homocistinúria/diagnóstico , Homocistinúria/terapia , Humanos , Hidroxocobalamina/administração & dosagem , Hidroxocobalamina/uso terapêutico , Lactente , Recém-Nascido , Masculino , Mutação , Triagem Neonatal , Fenótipo , Estudos Retrospectivos , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina B 12/genética , Deficiência de Vitamina B 12/terapia , Adulto Jovem
10.
Hum Mutat ; 38(10): 1365-1371, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28649782

RESUMO

Pathogenic variants in genes encoding components of the BRG1-associated factor (BAF) chromatin remodeling complex have been associated with intellectual disability syndromes. We identified heterozygous, novel variants in ACTL6A, a gene encoding a component of the BAF complex, in three subjects with varying degrees of intellectual disability. Two subjects have missense variants affecting highly conserved amino acid residues within the actin-like domain. Missense mutations in the homologous region in yeast actin were previously reported to be dominant lethal and were associated with impaired binding of the human ACTL6A to ß-actin and BRG1. A third subject has a splicing variant that creates an in-frame deletion. Our findings suggest that the variants identified in our subjects may have a deleterious effect on the function of the protein by disturbing the integrity of the BAF complex. Thus, ACTL6A gene mutation analysis should be considered in patients with intellectual disability, learning disabilities, or developmental language disorder.


Assuntos
Actinas/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Adolescente , Criança , Montagem e Desmontagem da Cromatina/genética , DNA Helicases/genética , Exoma , Face , Feminino , Deformidades Congênitas da Mão/fisiopatologia , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Micrognatismo/genética , Micrognatismo/fisiopatologia , Complexos Multiproteicos/genética , Proteínas Nucleares/genética , Ligação Proteica , Fatores de Transcrição/genética
11.
Am J Med Genet C Semin Med Genet ; 172(4): 367-383, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27813341

RESUMO

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility, low bone mass, and bone deformities. The majority of cases are caused by autosomal dominant pathogenic variants in the COL1A1 and COL1A2 genes that encode type I collagen, the major component of the bone matrix. The remaining cases are caused by autosomal recessively or dominantly inherited mutations in genes that are involved in the post-translational modification of type I collagen, act as type I collagen chaperones, or are members of the signaling pathways that regulate bone homeostasis. The main goals of treatment in OI are to decrease fracture incidence, relieve bone pain, and promote mobility and growth. This requires a multi-disciplinary approach, utilizing pharmacological interventions, physical therapy, orthopedic surgery, and monitoring nutrition with appropriate calcium and vitamin D supplementation. Bisphosphonate therapy, which has become the mainstay of treatment in OI, has proven beneficial in increasing bone mass, and to some extent reducing fracture risk. However, the response to treatment is not as robust as is seen in osteoporosis, and it seems less effective in certain types of OI, and in adult OI patients as compared to most pediatric cases. New pharmacological treatments are currently being developed, including anti-resorptive agents, anabolic treatment, and gene- and cell-therapy approaches. These therapies are under different stages of investigation from the bench-side, to pre-clinical and clinical trials. In this review, we will summarize the recent findings regarding the pharmacological and biological strategies for the treatment of patients with OI. © 2016 Wiley Periodicals, Inc.


Assuntos
Reabsorção Óssea/terapia , Osteogênese Imperfeita/terapia , Anabolizantes/uso terapêutico , Terapia Biológica/métodos , Reabsorção Óssea/tratamento farmacológico , Transplante de Células/métodos , Tratamento Farmacológico/métodos , Terapia Genética/métodos , Humanos
12.
Curr Opin Pediatr ; 28(6): 694-699, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27552071

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to summarize the development and recent advancements of newborn screening. RECENT FINDINGS: Early initiation of medical care has modified the outcome for many disorders that were previously associated with high morbidity (such as cystic fibrosis, primary immune deficiencies, and inborn errors of metabolism) or with significant neurodevelopmental disabilities (such as phenylketonuria and congenital hypothyroidism). The new era of mass spectrometry and next generation sequencing enables the expansion of the newborn screen panel, and will help to address technical issues such as turnaround time, and decreasing false-positive and false-negative rates for the testing. SUMMARY: The newborn screening program is a successful public health initiative that facilitates early diagnosis of treatable disorders to reduce long-term morbidity and mortality.


Assuntos
Testes Genéticos/história , Doenças do Recém-Nascido/história , Triagem Neonatal/história , Sequenciamento Completo do Genoma/história , Biomarcadores/sangue , Diagnóstico Precoce , Marcadores Genéticos , Testes Genéticos/métodos , Testes Genéticos/tendências , História do Século XX , História do Século XXI , Humanos , Recém-Nascido , Doenças do Recém-Nascido/sangue , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Triagem Neonatal/métodos , Triagem Neonatal/tendências , Estados Unidos , Sequenciamento Completo do Genoma/métodos , Sequenciamento Completo do Genoma/tendências
13.
J Cell Physiol ; 230(9): 2270-80, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25689118

RESUMO

Mesenchymal stem cells' differentiation into several lineages is coordinated by a complex of transcription factors and co-regulators which bind to specific gene promoters. The Chromatin-Related Mesenchymal Modulator, CHD9 demonstrated in vitro its ability for remodeling activity to reposition nucleosomes in an ATP-dependent manner. Epigenetically, CHD9 binds with modified H3-(K9me2/3 and K27me3). Previously, we presented a role for CHD9 with RNA Polymerase II (Pol II)-dependent transcription of tissue specific genes. Far less is known about CHD9 function in RNA Polymerase I (Pol I) related transcription of the ribosomal locus that also drives specific cell fate. We here describe a new form, the nucleolar CHD9 (n-CHD9) that is dynamically associated with Pol I, fibrillarin, and upstream binding factor (UBF) in the nucleoli, as shown by imaging and molecular approaches. Inhibitors of transcription disorganized the nucleolar compartment of transcription sites where rDNA is actively transcribed. Collectively, these findings link n-CHD9 with RNA pol I transcription in fibrillar centers. Using chromatin immunoprecipitation (ChIP) and tilling arrays (ChIP- chip), we find an association of n-CHD9 with Pol I related to rRNA biogenesis. Our new findings support the role for CHD9 in chromatin regulation and association with rDNA genes, in addition to its already known function in transcription control of tissue specific genes.


Assuntos
Diferenciação Celular/genética , DNA Ribossômico/genética , Células-Tronco Mesenquimais/citologia , Transativadores/genética , Animais , Células COS , Linhagem da Célula , Nucléolo Celular/genética , Nucléolo Celular/metabolismo , Cercopithecus aethiops , Cromatina/genética , Regulação da Expressão Gênica , Genes de RNAr , Células-Tronco Mesenquimais/metabolismo , Camundongos , Proteínas Pol1 do Complexo de Iniciação de Transcrição/genética , Proteínas Pol1 do Complexo de Iniciação de Transcrição/metabolismo , RNA Polimerase I/genética , RNA Polimerase I/metabolismo , Ribossomos/genética , Transativadores/metabolismo
14.
J Bone Miner Res ; 30(3): 489-98, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25251575

RESUMO

Osteogenesis imperfecta (OI) type V is characterized by increased bone fragility, long bone deformities, hyperplastic callus formation, and calcification of interosseous membranes. It is caused by a recurrent mutation in the 5' UTR of the IFITM5 gene (c.-14C > T). This mutation introduces an alternative start codon, adding 5 amino acid residues to the N-terminus of the protein. The mechanism whereby this novel IFITM5 protein causes OI type V is yet to be defined. To address this, we created transgenic mice expressing either the wild-type or the OI type V mutant IFITM5 under the control of an osteoblast-specific Col1a1 2.3-kb promoter. These mutant IFITM5 transgenic mice exhibited perinatal lethality, whereas wild-type IFITM5 transgenic mice showed normal growth and development. Skeletal preparations and radiographs performed on E15.5 and E18.5 OI type V transgenic embryos revealed delayed/abnormal mineralization and skeletal defects, including abnormal rib cage formation, long bone deformities, and fractures. Primary osteoblast cultures, derived from mutant mice calvaria at E18.5, showed decreased mineralization by Alizarin red staining, and RNA isolated from calvaria showed reduced expression of osteoblast differentiation markers such as Osteocalcin, compared with nontransgenic littermates and wild-type mice calvaria, consistent with the in vivo phenotype. Importantly, overexpression of wild-type Ifitm5 did not manifest a significant bone phenotype. Collectively, our results suggest that expression of mutant IFITM5 causes abnormal skeletal development, low bone mass, and abnormal osteoblast differentiation. Given that neither overexpression of the wild-type Ifitm5, as shown in our model, nor knock-out of Ifitm5, as previously published, showed significant bone abnormalities, we conclude that the IFITM5 mutation in OI type V acts in a neomorphic fashion.


Assuntos
Proteínas de Membrana/genética , Mutação , Animais , Camundongos , Camundongos Transgênicos
15.
Am J Ther ; 20(3): 311-4, 2013 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21317628

RESUMO

An 18-month-old male infant with oral albuterol intoxication was admitted to our pediatric emergency medicine unit with agitation, moderate hypokalemia (2.36 mEq/L), and hyperglycemia (180 mg/dL). His initial electrocardiogram showed sinus tachycardia with a low-amplitude T waves. He was admitted for observation, intravenous hydration was started with added potassium, blood glucose levels were closely monitored along with serum potassium and magnesium, and serial electrocardiography was performed. It should be stressed that as an oral bronchodilator, albuterol does not improve symptoms of asthma, and it can lead to severe complications, which can be avoided when this drug is delivered by inhalation or by a metered dose inhaler.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/envenenamento , Albuterol/envenenamento , Overdose de Drogas/diagnóstico , Administração Oral , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Albuterol/administração & dosagem , Overdose de Drogas/complicações , Humanos , Hiperglicemia/induzido quimicamente , Hipopotassemia/induzido quimicamente , Lactente , Masculino
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