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1.
Clin Genet ; 96(5): 461-467, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31368132

RESUMO

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or ß-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.

2.
Endocr Pathol ; 30(3): 237-245, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30772928

RESUMO

Neuroendocrine neoplasms (NENs) have been primarily associated with germline pathogenic variants in genes involved in chromatin remodeling (MEN1), cell cycle control (CDKN1B), PI3K/mTOR signaling (TSC1/2, PTEN) as well as pseudohypoxia (VHL, SDHx). Recent work has implicated various genes involved in DNA repair pathways in the pathophysiology of a subset of pancreatic neuroendocrine neoplasms, including BRCA2, via the homologous recombination pathway (HRD). To date, germline variants in other HRD pathway genes have not been described to contribute to NEN. PALB2, RAD51C, and BARD1 are additional tumor suppressor genes which also mediate repair of double stranded DNA breaks through the HRD pathway and are implicated in hereditary breast (PALB2; BARD1) and ovarian (RAD51C) cancer. Here we report three cases of NEN associated with germline pathogenic variants in PALB2 (pancreatic NEN), RAD51C (thymic NEN), and BARD1 (pancreaticoduodenal NEN) respectively, further linking the DNA repair pathway to NENs.

3.
Artigo em Inglês | MEDLINE | ID: mdl-30455668

RESUMO

Parathyroid carcinoma is a rare endocrine malignancy that is typically difficult to diagnose at presentation. Here, we report a 63 year-old man who had symptomatic hypercalcemia. Investigations revealed a thyroid nodule and a lateral neck mass that was biopsied and diagnosed as "suspicious for a neuroendocrine neoplasm." He underwent total thyroidectomy with central and left neck node dissection. Histology and immunohistochemistry revealed an intrathyroidal angioinvasive parathyroid carcinoma with lymph node metastases. The tumor showed loss of parafibromin expression; germline testing revealed no pathogenic germline variants of CDC73, suggesting either a cryptic germline variant or a sporadic malignancy. Multiple pulmonary nodules consistent with metastatic disease explained persistent hypercalcemia and the patient was treated with denosumab as well as Sorafenib resulting in early regression of the lung nodules. This case illustrates an unusual parathyroid carcinoma with respect to anatomic presentation and the importance of complete pathological workup in securing the diagnosis. The management of these rare malignancies is discussed.

4.
Circulation ; 138(12): 1195-1205, 2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-29959160

RESUMO

BACKGROUND: Implicit in the genetic evaluation of patients with suspected genetic diseases is the assumption that the genes evaluated are causative for the disease based on robust scientific and statistical evidence. However, in the past 20 years, considerable variability has existed in the study design and quality of evidence supporting reported gene-disease associations, raising concerns of the validity of many published disease-causing genes. Brugada syndrome (BrS) is an arrhythmia syndrome with a risk of sudden death. More than 20 genes have been reported to cause BrS and are assessed routinely on genetic testing panels in the absence of a systematic, evidence-based evaluation of the evidence supporting the causality of these genes. METHODS: We evaluated the clinical validity of genes tested by diagnostic laboratories for BrS by assembling 3 gene curation teams. Using an evidence-based semiquantitative scoring system of genetic and experimental evidence for gene-disease associations, curation teams independently classified genes as demonstrating limited, moderate, strong, or definitive evidence for disease causation in BrS. The classification of curator teams was reviewed by a clinical domain expert panel that could modify the classifications based on their independent review and consensus. RESULTS: Of 21 genes curated for clinical validity, biocurators classified only 1 gene ( SCN5A) as definitive evidence, whereas all other genes were classified as limited evidence. After comprehensive review by the clinical domain Expert panel, all 20 genes classified as limited evidence were reclassified as disputed with regard to any assertions of disease causality for BrS. CONCLUSIONS: Our results contest the clinical validity of all but 1 gene clinically tested and reported to be associated with BrS. These findings warrant a systematic, evidence-based evaluation for reported gene-disease associations before use in patient care.

5.
J Bone Miner Res ; 33(7): 1260-1271, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29669177

RESUMO

Osteogenesis imperfecta (OI) is a genetic bone disorder characterized by fractures, low bone mass, and skeletal fragility. It most commonly arises from dominantly inherited mutations in the genes COL1A1 and COL1A2 that encode the chains of type I collagen. A number of recent reports have suggested that mutations affecting the carboxyl-terminal propeptide cleavage site in the products of either COL1A1 or COL1A2 give rise to a form of OI characterized by unusually dense bones. We have assembled clinical, biochemical, and molecular data from 29 individuals from 8 families with 7 different mutations affecting the C-propeptide cleavage site. The phenotype was generally mild: The median height was ∼33th centile. Eighty percent of subjects had their first fracture by the age of 10 years, and one-third had a femoral or tibial fracture by the age of 25 years. Fractures continued into adulthood, though rates varied considerably. Healing was normal and rarely resulted in long bone deformity. One-third of subjects older than 15 years had scoliosis. The teeth and hearing were normal in most, and blue sclerae were not observed. Other features noted included fibro-osseous dysplasia of the mandible and Achilles tendon calcification. The mean spinal bone mineral density Z-score was +2.9 (SD 2.1) compared with -2.2 (0.7) in subjects with COL1A1 haploinsufficiency mutations. Bone mineral density distribution, assessed by quantitative backscattered electron imaging in bone showed higher levels of mineralization than found in any other disorder. Bone histology showed high trabecular volume and increased cortical thickness, with hyperosteoidosis and delayed mineralization. In vitro studies with cultured skin fibroblasts suggested that these mutations interfere with processing of the chain in which the sequence alteration occurs, but the C-propeptide is eventually cleaved (and detectable in blood), suggesting there are alternative sites of cleavage. The precise mechanism of the bony pathology is not yet clear. © 2018 American Society for Bone and Mineral Research.

6.
Am J Med Genet A ; 176(4): 925-935, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29436146

RESUMO

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

8.
Nat Genet ; 46(5): 503-509, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24686847

RESUMO

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.


Assuntos
Doenças Autoimunes do Sistema Nervoso/genética , RNA Helicases DEAD-box/genética , Interferon Tipo I/imunologia , Modelos Moleculares , Mutação/genética , Malformações do Sistema Nervoso/genética , Fenótipo , Transdução de Sinais/genética , Análise de Variância , Doenças Autoimunes do Sistema Nervoso/imunologia , Sequência de Bases , RNA Helicases DEAD-box/química , Ensaio de Desvio de Mobilidade Eletroforética , Exoma/genética , Células HEK293 , Humanos , Helicase IFIH1 Induzida por Interferon , Repetições de Microssatélites/genética , Dados de Sequência Molecular , Malformações do Sistema Nervoso/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Análise Espectral
9.
Am J Med Genet A ; 161A(8): 1833-52, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23813913

RESUMO

Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Proteínas 14-3-3/genética , Encéfalo/anormalidades , Transtornos do Comportamento Infantil/patologia , Transtornos Globais do Desenvolvimento Infantil/patologia , Cromossomos Humanos Par 17/genética , Duplicação Gênica , Proteínas Associadas aos Microtúbulos/genética , Adolescente , Adulto , Encéfalo/patologia , Criança , Transtornos do Comportamento Infantil/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Fenótipo
10.
Am J Hum Genet ; 92(4): 632-6, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23561849

RESUMO

Biochemical analysis and whole-exome sequencing identified mutations in the Golgi-localized UDP-galactose transporter SLC35A2 that define an undiagnosed X-linked congenital disorder of glycosylation (CDG) in three unrelated families. Each mutation reduced UDP-galactose transport, leading to galactose-deficient glycoproteins. Two affected males were somatic mosaics, suggesting that a wild-type SLC35A2 allele may be required for survival. In infancy, the commonly used biomarker transferrin showed abnormal glycosylation, but its appearance became normal later in childhood, without any corresponding clinical improvement. This may indicate selection against cells carrying the mutant allele. To detect other individuals with such mutations, we suggest transferrin testing in infancy. Here, we report somatic mosaicism in CDG, and our work stresses the importance of combining both genetic and biochemical diagnoses.


Assuntos
Defeitos Congênitos da Glicosilação/etiologia , Proteínas de Transporte de Monossacarídeos/genética , Mosaicismo , Mutação/genética , Uridina Difosfato Galactose/metabolismo , Transporte Biológico , Estudos de Casos e Controles , Criança , Pré-Escolar , Defeitos Congênitos da Glicosilação/metabolismo , Defeitos Congênitos da Glicosilação/patologia , Exoma/genética , Feminino , Glicosilação , Humanos , Masculino , Espectrometria de Massas por Ionização por Electrospray , Transferrina/análise , Transferrina/metabolismo
13.
Brain Res ; 1177: 59-65, 2007 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-17920045

RESUMO

Nonphotic phase shifts of the circadian clock in mammals are mediated by the intergeniculate leaflet (IGL) of the thalamus via a geniculohypothalamic projection to the suprachiasmatic nucleus. These shifts can be induced by arousing stimuli, such as wheel running, brain stimulation reward and foot shock. Because mesopontine cholinergic neurons are also activated by arousing stimuli, we tested the hypothesis that cholinergic input to the IGL mediates nonphotic phase shifts. Carbachol injected into the IGL of hamsters in their subjective day (CT8) induced phase advances similar to shifts that are induced by arousal at the same circadian time. Control injections of saline at CT8 did not advance phase similarly. Carbachol injections outside the IGL produced smaller shifts. Pre-injections of the muscarinic antagonist, atropine, reduced carbachol-induced phase advances relative to saline pre-injections. The results indicate that muscarinic input to the IGL can induce nonphotic phase shifts.


Assuntos
Carbacol/farmacologia , Ritmo Circadiano/efeitos dos fármacos , Corpos Geniculados/fisiologia , Agonistas Muscarínicos/farmacologia , Acetilcolina/agonistas , Acetilcolina/farmacologia , Animais , Atropina/farmacologia , Carbacol/administração & dosagem , Cricetinae , Corpos Geniculados/efeitos dos fármacos , Masculino , Mesocricetus , Atividade Motora/efeitos dos fármacos , Agonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacologia
14.
J Genet Couns ; 16(2): 201-10, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17277993

RESUMO

Adolescence is a period of challenges that can be more stressful for someone with a genetic condition. The purpose of this descriptive pilot study was to assess the informational needs of adolescents with a genetic condition. To our knowledge, this is the first study that has attempted to identify these needs. A convenience sample of adolescents between 12-19 years of age with either phenylketonuria or congenital adrenal hyperplasia and who had not previously received genetic counseling was recruited. Recruitment ended once the themes were saturated (n=17). A twenty item open/close-ended questionnaire was used to assess participants' knowledge of their genetic condition, what they wanted to know about their condition and in what manner. Almost all of the adolescents knew the name and genetic basis of their condition while most were aware of the risk of recurrence in a future pregnancy. Parents and doctors respectively, were identified as the primary and secondary sources of genetic information. Despite their evolving independence, almost all of the participants favoured receiving medical information with their parents present. The majority of participants felt that patients should begin receiving genetic information before the age of 12 years. Thematic analysis revealed that adolescents wanted to understand the science behind their condition, how their condition affects them, and how to manage it. The results highlight (i) the importance that adolescents place on parental involvement in their medical care (ii) that adolescents would like information about the genetics of their condition at a much younger age than when they usually receive genetic counseling and (iii) the benefits that can be gained by this patient population from receiving genetic counseling.


Assuntos
Hiperplasia Suprarrenal Congênita/psicologia , Necessidades e Demandas de Serviços de Saúde , Educação de Pacientes como Assunto , Fenilcetonúrias/psicologia , Adolescente , Hiperplasia Suprarrenal Congênita/genética , Adulto , Feminino , Aconselhamento Genético , Humanos , Masculino , Fenilcetonúrias/genética , Inquéritos e Questionários
15.
Am J Pathol ; 169(2): 459-70, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16877348

RESUMO

Excessive wall stretch of distensible hollow organs in cardiovascular and urinary systems can activate matrix metalloproteinases (MMPs), thereby releasing matrix neoepitopes and growth factor ligands, leading to ERK1/2 activation. However, the role of MMPs in mechanotransduction of ERK1/2 signaling in the bladder is unknown. We examined bladders undergoing sustained distension over time, which provides a novel platform for smooth muscle mechanotransduction studies. Bladder distension ex vivo caused increased proliferation and MMP activity. Conditioned medium from distended compared with undistended bladders induced proliferation in bladder smooth muscle cells (BSMCs). When conditioned medium from distended bladders was used to proteolyze collagen type I matrices, matrices augmented BSMC proliferation, which was inhibited if bladders were distended in presence of broad-spectrum MMP inhibitors. Distension of ex vivo bladders also induced ERK1/2 phosphorylation in situ, which was dependent on MMP activity in the intact bladder. Similarly, stretching BSMCs in vitro induced increases in ERK1/2 activation and ERK1/2-dependent proliferation under discrete mechanical conditions, and distension conditioned medium itself induced MMP-dependent ERK1/2 activation in BSMCs. Overall, stretch-induced proliferation and ERK1/2 signaling in bladder tissue and BSMCs likely depend on secreted MMP activity. Identification of intermediaries between MMPs and ERK1/2 may elaborate novel mechanisms underlying mechanotransduction in bladder smooth muscle.


Assuntos
Matriz Extracelular/metabolismo , Metaloproteinases da Matriz/metabolismo , Mecanotransdução Celular , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/enzimologia , Animais , Proliferação de Células , Células Cultivadas , Meios de Cultivo Condicionados , Feminino , Gelatinases/metabolismo , Substâncias de Crescimento/metabolismo , Técnicas In Vitro , Modelos Biológicos , Miócitos de Músculo Liso/metabolismo , Ratos , Ratos Sprague-Dawley , Bexiga Urinária/citologia
16.
In Vitro Cell Dev Biol Anim ; 42(5-6): 124-33, 2006 May-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16848631

RESUMO

Low oxygen tension (hypoxia) has been implicated in proliferation of vascular smooth muscle cells (SMCs) of the lung. Tissue hypoxia also occurs in the obstructed bladder. The extracellular-regulated kinase mitogen-activated protein kinase 1/2 (Erk1/2) pathway is induced in many cell types during hypoxia. We examined whether hypoxia (3% O2), compared with normoxia (21% O2), induces proliferation responses and activation of the Erk1/2 pathways in primary rat bladder smooth muscle cells (BSMCs). We show that hypoxia induces proliferation of BSMCs at 18 h and, although reduced at 22 h, still remained above normoxic levels. Hypoxia induced a strikingly transient activation of Erk1/2 that lasted only 10-30 min. However, inhibition of the transient Erk1/2 activity with a specific mitogen-activated protein kinase kinase 1 (MEK-1) inhibitor PD 98059 prevented subsequent hypoxia-induced proliferation at 18 h. Interestingly, inhibition of general matrix metalloproteinase (MMP) activity, using either doxycycline or GM 6001, prevented both transient Erk1/2 activity and subsequent proliferation in response to hypoxia. Furthermore, MMP-7 (matrilysin) is activated in the conditioned medium (CM) of BSMCs at 10-20 min of hypoxia. In addition, MMP-7 was also transcriptionally induced at 6 h of hypoxia in an Erk1/2-dependent manner. Moreover, transient Erk1/2 activation and BSMC proliferation were both dependent on epidermal growth factor receptor (EGFR/HER1) but not neu receptor (HER2/ERB2) autophosphorylation. We conclude that hypoxia leads to Erk1/2 activation, which appears to modulate BSMC proliferation through MMP-7-and EGFR-mediated mechanisms.


Assuntos
Receptores ErbB/metabolismo , Metaloproteinase 7 da Matriz/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso/enzimologia , Bexiga Urinária/citologia , Animais , Hipóxia Celular , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática , Receptores ErbB/fisiologia , Flavonoides/farmacologia , Regulação da Expressão Gênica , MAP Quinase Quinase 1/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/fisiologia , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/fisiologia , Músculo Liso/citologia , Músculo Liso/efeitos dos fármacos , Fosforilação , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
17.
Cell Tissue Res ; 326(1): 149-58, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16705451

RESUMO

Excessive stretch of the bladder can lead to wall thickening including the growth of bladder smooth muscle cells (BSMC). Only three phospho-proteins (JNK, p38, and PI3K) have been previously shown to participate in stretch-induced BSMC growth. CD1 mouse bladders were hyper- or non-distended by our ex vivo bladder distention model and screened, by a commercial screening method, for phosphorylated signaling proteins. This uncovered a factor previously unexamined for its role in bladder stretch injury: signal transducer and activator of transcription 3 (STAT3). STAT3 was assessed for its role in mitogen- and stretch-induced BSMC proliferation. Proliferation was assessed by 3H-thymidine incorporation/cell counting in response to mitogenic stimulation or to stretch on silastic collagen or carboxyl-coated membranes. JAK2, upstream of STAT3, was inhibited by AG490 (2 microM). Ex vivo distention of bladders activated a discrete number of kinases, including two MAPK pathways (JNK and ERK2) and STAT3. STAT3 signaling was activated during hyperdistention of intact bladder and by stretch and mitogenic treatments of BSMC in vitro. JAK2/STAT3 inhibition by AG490 blocked mitogen- and stretch-induced BSMC proliferation. Thus, BSMC stretch responses may involve the recruitment of both growth factor and mechanically induced BSMC growth responses integrated by a common signaling pathway, STAT3.


Assuntos
Sistema de Sinalização das MAP Quinases , Miócitos de Músculo Liso/metabolismo , Fator de Transcrição STAT3/metabolismo , Bexiga Urinária/lesões , Bexiga Urinária/metabolismo , Animais , Proliferação de Células , Inibidores Enzimáticos , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Miócitos de Músculo Liso/patologia , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/antagonistas & inibidores , Tirfostinas/farmacologia , Bexiga Urinária/patologia
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