Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 30
Filtrar
1.
Am J Hum Genet ; 103(3): 358-366, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30122538

RESUMO

While consensus regarding the return of secondary genomic findings in the clinical setting has been reached, debate about such findings in the research setting remains. We developed a hybrid, research-clinical translational genomics process for research exome data coupled with a CLIA-validated secondary findings analysis. Eleven intramural investigators from ten institutes at the National Institutes of Health piloted this process. Nearly 1,200 individuals were sequenced and 14 secondary findings were identified in 18 participants. Positive secondary findings were returned by a genetic counselor following a standardized protocol, including referrals for specialty follow-up care for the secondary finding local to the participants. Interviews were undertaken with 13 participants 4 months after receipt of a positive report. These participants reported minimal psychologic distress within a process to assimilate their results. Of the 13, 9 reported accessing the recommended health care services. A sample of 107 participants who received a negative findings report were surveyed 4 months after receiving it. They demonstrated good understanding of the negative secondary findings result and most expressed reassurance (64%) from that report. However, a notable minority (up to 17%) expressed confusion regarding the distinction of primary from secondary findings. This pilot shows it is feasible to couple CLIA-compliant secondary findings to research sequencing with minimal harms. Participants managed the surprise of a secondary finding with most following recommended follow up, yet some with negative findings conflated secondary and primary findings. Additional work is needed to understand barriers to follow-up care and help participants distinguish secondary from primary findings.


Assuntos
Exoma/genética , Feminino , Aconselhamento Genético/métodos , Genômica/métodos , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Projetos Piloto
2.
PLoS Biol ; 16(7): e2005263, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30036371

RESUMO

Bones at different anatomical locations vary dramatically in size. For example, human femurs are 20-fold longer than the phalanges in the fingers and toes. The mechanisms responsible for these size differences are poorly understood. Bone elongation occurs at the growth plates and advances rapidly in early life but then progressively slows due to a developmental program termed "growth plate senescence." This developmental program includes declines in cell proliferation and hypertrophy, depletion of cells in all growth plate zones, and extensive underlying changes in the expression of growth-regulating genes. Here, we show evidence that these functional, structural, and molecular senescent changes occur earlier in the growth plates of smaller bones (metacarpals, phalanges) than in the growth plates of larger bones (femurs, tibias) and that this differential aging contributes to the disparities in bone length. We also show evidence that the molecular mechanisms that underlie the differential aging between different bones involve modulation of critical paracrine regulatory pathways, including insulin-like growth factor (Igf), bone morphogenetic protein (Bmp), and Wingless and Int-1 (Wnt) signaling. Taken together, the findings reveal that the striking disparities in the lengths of different bones, which characterize normal mammalian skeletal proportions, is achieved in part by modulating the progression of growth plate senescence.


Assuntos
Envelhecimento/fisiologia , Osso e Ossos/anatomia & histologia , Cartilagem/crescimento & desenvolvimento , Lâmina de Crescimento/crescimento & desenvolvimento , Animais , Desenvolvimento Ósseo , Proliferação de Células , Condrócitos/patologia , Extremidades/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Hipertrofia , Camundongos Endogâmicos C57BL , Comunicação Parácrina , Ratos Sprague-Dawley , Tíbia/crescimento & desenvolvimento
3.
Curr Opin Pediatr ; 33(4): 458-463, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34101704

RESUMO

PURPOSE OF REVIEW: Short stature is a common clinical manifestation in children. Yet, a cause is often unidentifiable in the majority of children with short stature by a routine screening approach. The purpose of this review is to describe the optimal genetic approach for evaluating short stature, challenges of genetic testing, and recent advances in genetic testing for short stature. RECENT FINDINGS: Genetic testing, such as karyotype, chromosomal microarray, targeted gene sequencing, or exome sequencing, has served to identify the underlying genetic causes of short stature. When determining which short stature patient would benefit from genetic evaluation, it is important to consider whether the patient would have a single identifiable genetic cause. Specific diagnoses permit clinicians to predict responses to growth hormone treatment, to understand the phenotypic spectrum, and to understand any associated co-morbidities. SUMMARY: The continued progress in the field of genetics and enhanced capabilities provided by genetic testing methods expands the ability of physicians to evaluate children with short stature for underlying genetic defects. Continued effort is needed to elaborate new genetic causes of linear growth disorders, therefore, we expand the list of known genes for short stature, which will subsequently increase the rate of genetic diagnosis for children with short stature.


Assuntos
Nanismo , Estatura/genética , Criança , Nanismo/diagnóstico , Nanismo/genética , Testes Genéticos , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Humanos , Sequenciamento do Exoma
4.
Genet Med ; 22(8): 1329-1337, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32341572

RESUMO

PURPOSE: Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions. METHODS: Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH. RESULTS: We identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that cosegregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in three unrelated families with IHH. CONCLUSION: The findings indicate that variants in DLG2/PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion.


Assuntos
Hormônio Liberador de Gonadotropina , Hipogonadismo , Hormônio Liberador de Gonadotropina/genética , Guanilato Quinases , Humanos , Hipogonadismo/genética , Proteínas , Transdução de Sinais , Proteínas Supressoras de Tumor , Sequenciamento do Exoma
5.
Clin Genet ; 95(1): 160-164, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30281152

RESUMO

In many children with short stature, the etiology of the decreased linear growth remains unknown. We sought to identify the underlying genetic etiology in a patient with short stature, irregular growth plates of the proximal phalanges, developmental delay, and mildly dysmorphic facial features. Exome sequencing identified a de novo, heterozygous, nonsense mutation (c.1606C>T:p.R536X) in QRICH1. In vitro studies confirmed that the mutation impaired expression of the QRICH1 protein. SiRNA-mediated knockdown of Qrich1 in primary mouse epiphyseal chondrocytes caused downregulation of gene expression associated with hypertrophic differentiation. We then identified an unrelated individual with another heterozygous de novo nonsense mutation in QRICH1 who had a similar phenotype. A recently published study identified QRICH1 mutations in three patients with developmental delay, one of whom had short stature. Our findings indicate that QRICH1 mutations cause not only developmental delay but also a chondrodysplasia characterized by diminished linear growth and abnormal growth plate morphology due to impaired growth plate chondrocyte hypertrophic differentiation.


Assuntos
Condrogênese/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Proteínas dos Microtúbulos/genética , Osteocondrodisplasias/genética , Fatores de Transcrição/genética , Animais , Criança , Pré-Escolar , Condrócitos/metabolismo , Condrócitos/patologia , Códon sem Sentido/genética , Deficiências do Desenvolvimento/patologia , Exoma/genética , Feminino , Lâmina de Crescimento/crescimento & desenvolvimento , Lâmina de Crescimento/patologia , Heterozigoto , Humanos , Lactente , Masculino , Camundongos , Mutação/genética , Osteocondrodisplasias/patologia
6.
Curr Opin Pediatr ; 30(4): 541-547, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29787394

RESUMO

PURPOSE OF REVIEW: Genome-wide approaches including genome-wide association studies as well as exome and genome sequencing represent powerful new approaches that have improved our ability to identify genetic causes of human disorders. The purpose of this review is to describe recent advances in the genetic causes of short stature. RECENT FINDINGS: In addition to SHOX deficiency which is one of the most common causes of isolated short stature, PAPPA2, ACAN, NPPC, NPR2, PTPN11 (and other rasopathies), FBN1, IHH and BMP2 have been identified in isolated growth disorders with or without other mild skeletal findings. In addition, novel genetic causes of syndromic short stature have been discovered, including pathogenic variants in BRCA1, DONSON, AMMECR1, NFIX, SLC25A24, and FN1. SUMMARY: Isolated growth disorders are often monogenic. Specific genetic causes typically have specific biochemical and/or phenotype characteristics which are diagnostically helpful. Identification of additional subjects with a specific genetic cause of short stature often leads to a broadening of the known clinical spectrum for that condition. The identification of novel genetic causes of short stature has provided important insights into the underlying molecular mechanisms of growth failure.


Assuntos
Nanismo/diagnóstico , Nanismo/genética , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Criança , Marcadores Genéticos , Predisposição Genética para Doença , Testes Genéticos , Estudo de Associação Genômica Ampla , Humanos , Sequenciamento do Exoma , Sequenciamento Completo do Genoma
7.
Clin Endocrinol (Oxf) ; 83(6): 977-84, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25411136

RESUMO

CONTEXT: The primary preoperative method for distinguishing malignant from benign thyroid nodules is fine-needle aspiration (FNA) cytology, but it is frequently inconclusive. Midkine (MDK) is a heparin-binding growth factor, which is overexpressed in papillary thyroid carcinoma (PTC). OBJECTIVE: We measured MDK concentrations in FNA samples from benign and malignant thyroid nodules to explore the possibility that MDK measurement might aid in the evaluation of thyroid nodules. DESIGN: 35 subjects underwent preoperative FNA of 45 thyroid nodules, followed by thyroidectomy, providing a histological diagnosis. FNA needle contents were first expressed for cytology, and then, the needle was washed with buffer for immunoassay. In 46 subjects without preoperative FNA samples, FNA was performed ex vivo on 62 nodules within surgically excised thyroid tissue. MEASUREMENTS: MDK was measured using a high-sensitivity sandwich ELISA and normalized to thyroglobulin (Tg) concentration in the sample to adjust for tissue content in the aspirate. RESULTS: The MDK/Tg ratio was higher in 18 PTCs than in 87 benign nodules (204 ± 106 vs 1·2 ± 0·3 ng/mg, mean ± SEM, P < 0·001). Using a threshold of 10 ng/mg, the sensitivity and specificity of the MDK/Tg ratio for diagnosis of PTC were 67% and 99%, respectively. All follicular variant PTCs had a MDK/Tg ratio <10 ng/mg. CONCLUSIONS: The findings indicate that, in FNA samples, the MDK/Tg ratio in PTC is greater than in benign thyroid nodules, raising the possibility that this approach might provide adjunctive diagnostic or prognostic information to complement existing approaches.


Assuntos
Biópsia por Agulha Fina/métodos , Citocinas/análise , Tireoglobulina/análise , Nódulo da Glândula Tireoide/química , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Midkina
8.
JCEM Case Rep ; 2(5): luae050, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38660487

RESUMO

We report a case of persistent gynecomastia in a healthy 20-year-old man after 1 month of low-dose finasteride. Finasteride was discontinued after 2 months, and gynecomastia was unchanged 5 months after drug withdrawal. The gynecomastia regressed but did not resolve after 6 months of treatment with raloxifene, a selective estrogen receptor modulator. One year later, bilateral mammoplasty was performed to remove the remaining breast tissue. Finasteride, a 5-alpha-reductase inhibitor, is widely used for the treatment of androgenetic alopecia. Gynecomastia is an expected side effect of this therapy given its mechanism of action. However, only 8 cases of gynecomastia have been reported with low-dose (1 mg daily) finasteride treatment since its approval for androgenetic alopecia in 1997. This raises the concern that gynecomastia resulting from low-dose finasteride is significantly underreported, causing inadequately informed patients. Further, because of the risk of gynecomastia, it is important for prescribing physicians to counsel patients regarding this complication and to consider early intervention when finasteride-induced gynecomastia first arises to prevent fibrosis and thus irreversible gynecomastia.

9.
J Clin Endocrinol Metab ; 108(9): e663-e670, 2023 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-37029976

RESUMO

Accelerated early growth and early timing of puberty or pubertal variant have been noticed as risk factors for metabolic syndrome, more frequently observed in children born small for gestational age (SGA) or children with premature adrenarche (PA). Children with SGA, especially if they make an accelerated catch-up growth in early life, carry a higher risk for long-term metabolic consequences, such as type 2 diabetes, insulin resistance, and cardiovascular diseases. Furthermore, multiple studies support that these children, either born SGA or with a history of PA, may have earlier pubertal timing, which is also associated with various metabolic risks. This review aims to summarize the recent studies investigating the association between early infantile growth, the timing of puberty, and metabolic risks to expand our knowledge and gain more insight into the underlying pathophysiology.


Assuntos
Diabetes Mellitus Tipo 2 , Síndrome Metabólica , Recém-Nascido , Feminino , Humanos , Criança , Diabetes Mellitus Tipo 2/complicações , Puberdade/fisiologia , Recém-Nascido Pequeno para a Idade Gestacional , Retardo do Crescimento Fetal , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/etiologia
10.
JCI Insight ; 8(9)2023 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-36927955

RESUMO

Overgrowth syndromes can be caused by pathogenic genetic variants in epigenetic writers, such as DNA and histone methyltransferases. However, no overgrowth disorder has previously been ascribed to variants in a gene that acts primarily as an epigenetic reader. Here, we studied a male individual with generalized overgrowth of prenatal onset. Exome sequencing identified a hemizygous frameshift variant in Spindlin 4 (SPIN4), with X-linked inheritance. We found evidence that SPIN4 binds specific histone modifications, promotes canonical WNT signaling, and inhibits cell proliferation in vitro and that the identified frameshift variant had lost all of these functions. Ablation of Spin4 in mice recapitulated the human phenotype with generalized overgrowth, including increased longitudinal bone growth. Growth plate analysis revealed increased cell proliferation in the proliferative zone and an increased number of progenitor chondrocytes in the resting zone. We also found evidence of decreased canonical Wnt signaling in growth plate chondrocytes, providing a potential explanation for the increased number of resting zone chondrocytes. Taken together, our findings provide strong evidence that SPIN4 is an epigenetic reader that negatively regulates mammalian body growth and that loss of SPIN4 causes an overgrowth syndrome in humans, expanding our knowledge of the epigenetic regulation of human growth.


Assuntos
Epigênese Genética , Genes Ligados ao Cromossomo X , Masculino , Humanos , Camundongos , Animais , Síndrome , Proteínas de Ciclo Celular , Mamíferos
11.
J Pediatr Endocrinol Metab ; 35(11): 1337-1344, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36193720

RESUMO

BACKGROUND: The use of stimulant medications for treatment of ADHD has raised concern as to whether they adversely impact linear growth. Previous studies have indicated that stimulant medications may suppress growth for a short period after treatment initiation; however, more information is needed to evaluate the long-term effects on final adult stature. This mini review aims to evaluate the effect of stimulant medications on final adult height in children with ADHD. CONTENTS: We performed a literature review across PubMed/MEDLINE database. Only articles that included data on final adult height or near final adult height (age≥16 or 17 years) were included. SUMMARY: Early studies investigating the long-term impacts of stimulant medications observed growth suppression during the active treatment period, but when comparing final adult height, there was no difference between the control and ADHD groups. A recent larger comprehensive study (Multimodal Treatment of ADHD study) has suggested that the long-term use of significant doses of stimulants during childhood may compromise final adult height to a clinically significant degree when comparing adult height across three long-term patterns of stimulant treatment (Consistent, Intermittent, Negligible). The consistent use subgroup was significantly shorter than other subgroups. OUTLOOK: For children with ADHD, a significant long-term dose of stimulant treatment should be used with caution to avoid diminishing adult height potential. Pediatric endocrinologists should consider chronic use of stimulants as a factor contributing to reduced adult height.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Criança , Adulto , Humanos , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Estatura , Terapia Combinada , Bases de Dados Factuais
12.
Nat Commun ; 13(1): 700, 2022 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-35121733

RESUMO

SP7/Osterix is a transcription factor critical for osteoblast maturation and bone formation. Homozygous loss-of-function mutations in SP7 cause osteogenesis imperfecta type XII, but neomorphic (gain-of-new-function) mutations of SP7 have not been reported in humans. Here we describe a de novo dominant neomorphic missense variant (c.926 C > G:p.S309W) in SP7 in a patient with craniosynostosis, cranial hyperostosis, and long bone fragility. Histomorphometry shows increased osteoblasts but decreased bone mineralization. Mice with the corresponding variant also show a complex skeletal phenotype distinct from that of Sp7-null mice. The mutation alters the binding specificity of SP7 from AT-rich motifs to a GC-consensus sequence (typical of other SP family members) and produces an aberrant gene expression profile, including increased expression of Col1a1 and endogenous Sp7, but decreased expression of genes involved in matrix mineralization. Our study identifies a pathogenic mechanism in which a mutation in a transcription factor shifts DNA binding specificity and provides important in vivo evidence that the affinity of SP7 for AT-rich motifs, unique among SP proteins, is critical for normal osteoblast differentiation.


Assuntos
Doenças Ósseas/genética , Osso e Ossos/metabolismo , Regulação da Expressão Gênica , Mutação , Fator de Transcrição Sp7/genética , Animais , Doenças Ósseas/metabolismo , Diferenciação Celular/genética , Linhagem Celular , Células Cultivadas , Criança , Células HEK293 , Humanos , Hibridização In Situ , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/citologia , Osteoblastos/metabolismo , Fator de Transcrição Sp7/metabolismo , Microtomografia por Raio-X
14.
Front Genet ; 12: 697549, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456972

RESUMO

PURPOSE: Congenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown. METHODS: We studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) (n = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups. RESULTS: First, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, P = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, P = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband's condition with a monogenic etiology (de novo mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, P = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, P = 0.01). CONCLUSION: Our findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology.

15.
Ann Pediatr Endocrinol Metab ; 24(1): 2-14, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30943674

RESUMO

Linear growth occurs at the growth plate. Therefore, genetic defects that interfere with the normal function of the growth plate can cause linear growth disorders. Many genetic causes of growth disorders have already been identified in humans. However, recent genome-wide approaches have broadened our knowledge of the mechanisms of linear growth, not only providing novel monogenic causes of growth disorders but also revealing single nucleotide polymorphisms in genes that affect height in the general population. The genes identified as causative of linear growth disorders are heterogeneous, playing a role in various growth-regulating mechanisms including those involving the extracellular matrix, intracellular signaling, paracrine signaling, endocrine signaling, and epigenetic regulation. Understanding the underlying genetic defects in linear growth is important for clinicians and researchers in order to provide proper diagnoses, management, and genetic counseling, as well as to develop better treatment approaches for children with growth disorders.

16.
PLoS One ; 14(10): e0224103, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31648221

RESUMO

BACKGROUND: Midkine (MDK), one of the heparin-binding growth factors, is highly expressed in multiple organs during embryogenesis. Plasma concentrations have been reported to be elevated in patients with a variety of malignancies, in adults with obesity, and in children with short stature, diabetes, and obesity. However, the concentrations in healthy children and their relationships to age, nutrition, and linear growth have not been well studied. SUBJECTS AND METHODS: Plasma MDK was measured by immunoassay in 222 healthy, normal-weight children (age 0-18 yrs, 101 boys), 206 healthy adults (age 18-91 yrs, 60 males), 61 children with BMI ≥ 95th percentile (age 4-18 yrs, 20 boys), 20 girls and young women with anorexia nervosa (age 14-23 yrs), and 75 children with idiopathic short stature (age 3-18 yrs, 42 boys). Body fat was evaluated by dual-energy X-ray absorptiometry (DXA) in a subset of subjects. The associations of MDK with age, sex, adiposity, race/ethnicity and stature were evaluated. RESULTS: In healthy children, plasma MDK concentrations declined with age (r = -0.54, P < 0.001) with values highest in infants. The decline occurred primarily during the first year of life. Plasma MDK did not significantly differ between males and females or between race/ethnic groups. MDK concentrations were not correlated with BMI SDS, fat mass (kg) or percent total body fat, and no difference in MDK was found between children with anorexia nervosa, healthy weight and obesity. For children with idiopathic short stature, MDK concentrations did not differ significantly from normal height subjects, or according to height SDS or IGF-1 SDS. CONCLUSIONS: In healthy children, plasma MDK concentrations declined with age and were not significantly associated with sex, adiposity, or stature-for-age. These findings provide useful reference data for studies of plasma MDK in children with malignancies and other pathological conditions.


Assuntos
Adiposidade , Biomarcadores/sangue , Nanismo/diagnóstico , Transtornos do Crescimento/diagnóstico , Midkina/sangue , Obesidade/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Pré-Escolar , Nanismo/sangue , Feminino , Transtornos do Crescimento/sangue , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Adulto Jovem
17.
Endocrinology ; 159(3): 1469-1478, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29390136

RESUMO

Growth plate chondrocytes undergo sequential differentiation to form the resting zone, the proliferative zone (PZ), and the hypertrophic zone (HZ). The important role of microRNAs (miRNAs) in the growth plate was previously revealed by cartilage-specific ablation of Dicer, an enzyme essential for biogenesis of many miRNAs. To identify specific miRNAs that regulate differentiation of PZ chondrocytes to HZ chondrocytes, we microdissected individual growth plate zones from juvenile rats and performed miRNA profiling using a solution hybridization method and miRNA sequencing. Thirty-four miRNAs were differentially expressed between the PZ and the HZ, and we hypothesized that some of the miRNAs that are preferentially expressed in the PZ may promote proliferation and inhibit hypertrophic differentiation. Consistent with this hypothesis, transfection of inhibitors for four of these miRNAs (mir-369-3p, mir-374-5p, mir-379-5p, and mir-503-5p) decreased proliferation in primary epiphyseal chondrocytes. The inhibitors for three of these miRNAs (mir-374-5p, mir-379-5p, and mir-503-5p) also increased expression of multiple genes that are associated with chondrocyte hypertrophic differentiation. We next hypothesized that preferential expression of these miRNAs in the PZ is driven by the parathyroid hormone-related protein (PTHrP) concentration gradient across the growth plate. Consistent with this hypothesis, treatment of primary chondrocytes with a parathyroid hormone (PTH)/PTHrP receptor agonist, PTH1-34, increased expression of mir-374-5p, mir-379-5p, and mir-503-5p. Taken together, our findings suggest that the PTHrP concentration gradient across the growth plate induces differential expression of mir-374-5p, mir-379-5p, and mir-503-5p between the PZ and the HZ. In the PZ, the higher expression levels of these miRNAs promote proliferation and inhibit hypertrophic differentiation. In the HZ, downregulation of these miRNAs inhibits proliferation and promotes hypertrophic differentiation.


Assuntos
Diferenciação Celular , Proliferação de Células , Condrócitos/citologia , Lâmina de Crescimento/metabolismo , Hipertrofia/fisiopatologia , MicroRNAs/metabolismo , Animais , Ciclo Celular , Células Cultivadas , Condrócitos/metabolismo , Regulação da Expressão Gênica , Lâmina de Crescimento/crescimento & desenvolvimento , Humanos , Hipertrofia/genética , Hipertrofia/metabolismo , Masculino , MicroRNAs/genética , Ratos , Ratos Sprague-Dawley
20.
Horm Res Paediatr ; 88(1): 22-37, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28334714

RESUMO

Idiopathic short stature is a common condition with a heterogeneous etiology. Advances in genetic methods, including genome sequencing techniques and bioinformatics approaches, have emerged as important tools to identify the genetic defects in families with monogenic short stature. These findings have contributed to the understanding of growth regulation and indicate that growth plate chondrogenesis, and therefore linear growth, is governed by a large number of genes important for different signaling pathways and cellular functions, including genetic defects in hormonal regulation, paracrine signaling, cartilage matrix, and fundamental cellular processes. In addition, mutations in the same gene can cause a wide phenotypic spectrum depending on the severity and mode of inheritance of the mutation.
.


Assuntos
Estatura/genética , Desenvolvimento Infantil/fisiologia , Transtornos do Crescimento/diagnóstico , Criança , Condrogênese/genética , Genoma Humano , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/genética , Humanos , Fator de Crescimento Insulin-Like I/genética , Mutação
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa