Assuntos
Arginina/administração & dosagem , Nanismo Hipofisário/história , Insulina/sangue , Pediatria/história , Publicações Periódicas como Assunto/história , Criança , Nanismo Hipofisário/sangue , Nanismo Hipofisário/tratamento farmacológico , Hormônio do Crescimento/sangue , História do Século XX , Humanos , Infusões IntravenosasRESUMO
BACKGROUND: The growth-promoting effects of IGF-I is mediated through the IGF-I receptor (IGF1R), a widely expressed cell-surface tyrosine kinase receptor. IGF1R copy number variants (CNV) can cause pre- and postnatal growth restriction or overgrowth. METHODS: Whole exome sequence (WES), chromosomal microarray, and targeted IGF1R gene analyses were performed on 3 unrelated children who share features of small for gestational age, short stature, and elevated serum IGF-I, but otherwise had clinical heterogeneity. Fluorescence-activated cell sorting (FACS) analysis of cell-surface IGF1R was performed on live primary cells derived from the patients. RESULTS: Two novel IGF1R CNV and a heterozygous IGF1R nonsense variant were identified in the 3 patients. One CNV (4.492 Mb) was successfully called from WES, utilizing eXome-Hidden Markov Model (XHMM) analysis. FACS analysis of cell-surface IGF1R on live primary cells derived from the patients demonstrated a â¼50% reduction in IGF1R availability associated with the haploinsufficiency state. CONCLUSION: In addition to conventional methods, IGF1R CNV can be identified from WES data. FACS analysis of live primary cells is a promising method for efficiently evaluating and screening for IGF1R haploinsufficiency. Further investigations are necessary to delineate how comparable IGF1R availability leads to the wide spectrum of clinical phenotypes and variable responsiveness to rhGH therapy.
Assuntos
Transtornos do Crescimento/genética , Haploinsuficiência , Receptores de Somatomedina/genética , Criança , Exoma , Feminino , Transtornos do Crescimento/diagnóstico , Humanos , Receptor IGF Tipo 1Assuntos
Hormônio do Crescimento/deficiência , Hormônio do Crescimento/fisiologia , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/fisiologia , Congressos como Assunto , Equador , Humanos , Síndrome de Laron/genética , Síndrome de Laron/metabolismo , Peptídeos/química , UniversidadesRESUMO
Laron syndrome (LS) is a genetic disorder caused by mutations in the growth hormone receptor (GHR) gene. The most frequent GHR mutation is E180splice (rs121909360), which was initially found in an inbred population of Spanish descent in Ecuador and subsequently in Israel, Brazil, Chile, and the United States. The aim of the present study is to determine if the E180splice mutation arose from a common origin. We studied 22 patients with LS from Ecuador, Israel (of Moroccan origin), Brazil, Chile, and the United States (of Mexican origin) who were homozygous for the E180splice mutation and compared them to control individuals for markers surrounding the GHR, intragenic polymorphisms, and Y-chromosome STR. An identical haplotype was found in all but one of the subjects carrying the E180splice mutation: D5S665: 150/150; D5S2082: 192/192; D5S2087: 246/246; rs6179 G/G; and rs6180 C/C. One patient differed from the others only at D5S2082 (168/192). This haplotype is rare (~1%) in control individuals and confirmed that the E180splice-associated haplotype was not derived from independent origins but represented recombination from a common ancestor. The analysis of paternal lineage markers showed that 50% belong to haplogroup R1b (found in Portugal and Spain) and 40% to haplogroups J and E (typical in the Middle East and in Eastern European Jews). The germline E180Splice mutation appears to have originated from a single common ancestor. The presence of Y-chromosome markers associated with Sephardic populations in persons harboring the E180splice mutation provides genetic evidence in support of the historical tracking of the exodus of this specific population.
Assuntos
Síndrome de Laron/diagnóstico , Síndrome de Laron/genética , Mutação , Sítios de Splice de RNA , Receptores da Somatotropina/genética , Brasil , Cromossomos Humanos Y , DNA Mitocondrial , Equador , Feminino , Haplótipos , Homozigoto , Humanos , Israel , Judeus/genética , Masculino , Repetições de MicrossatélitesRESUMO
CONTEXT: Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported in a patient who carried a p.Ala630Pro missense mutation in the Src homology 2 (SH2) domain, results in a rare clinical condition of GH insensitivity (GHI), IGF-I deficiency (IGFD), and severe immune dysregulation manifesting as progressive worsening of pulmonary function. PATIENT: The new patient presented with severe cutaneous eczema, episodic infections in the first years of life, and autoimmune thyroiditis. Immunological evaluation revealed T lymphopenia, but severe pulmonary symptoms were notably absent. She concomitantly exhibited pronounced growth failure, reaching an adult height of 124.7 cm [-5.90 SD score (SDS)]. Endocrine evaluations (normal provocative GH tests; low serum IGF-I, -3.7 SDS, and IGF-binding protein-3, -4.5 SDS) were consistent with GHI and IGFD. RESULTS: Analysis of the STAT5B gene revealed a novel homozygous missense mutation, p.Phe646Ser, located within the ßD' strand of the SH2 domain. Reconstitution studies demonstrated expression of the p.Phe646Ser variant was less robust than wild type but, in contrast to the previously described STAT5B p.Ala630Pro SH2 mutation, could be phosphorylated in response to GH and interferon-γ. The phosphorylated p.Phe646Ser, however, could not drive transcription. CONCLUSION: A novel STAT5B p.Phe646Ser mutation has been identified in a patient with clinical characteristics of STAT5b deficiency. Only the second STAT5B missense mutation identified, its lack of transcriptional activities despite GH-induced phosphorylation, confirms the crucial role of STAT5b for regulating the expression of IGF1 and provides insights into the importance of the SH2 ßD' strand for full STAT5b transcriptional activities. Whether the phosphorylated p.Phe646Ser variant retained functions that prevented pulmonary distress remains unresolved.
Assuntos
Nanismo Hipofisário/genética , Doenças do Sistema Imunitário/genética , Fator de Crescimento Insulin-Like I/deficiência , Mutação de Sentido Incorreto , Fator de Transcrição STAT5/genética , Tireoidite Autoimune/genética , Análise Mutacional de DNA , Feminino , Humanos , Fator de Crescimento Insulin-Like I/genética , Pneumopatias/genética , Adulto Jovem , Domínios de Homologia de src/genéticaRESUMO
OBJECTIVE: To describe the clinical and biochemical features, and perform molecular analysis for candidate abnormalities in a novel familial syndrome of intrauterine growth retardation (IUGR), failure of an adolescent growth spurt with proportional adult short stature, minimal subluxation of the 5th metacarpal-phalangeal joint, and adult-onset insulin-resistant diabetes unrelated to obesity or other manifestations of metabolic syndrome (MS). DESIGN: Detailed clinical history, auxological, biochemical, radiological, and molecular studies, including DNA analysis and in vitro study of the GH/IGF1 pathway. MATERIALS AND METHODS: Ten affected adults from two generations of five related families were studied in detail, and information obtained about nine other likely affected individuals. RESULTS: Height Z-scores ranged from -7.3 to -3.8. Unaffected parents of the older generation and frequency of confirmed and suspected instances of the syndrome in the two generations studied is consistent with autosomal recessive inheritance. Insulin resistance was uniformly present in seven subjects tested who were not taking insulin. Diabetes severity did not correlate with overweight. Subjects did not have other typical manifestations of MS such as substantial hyperlipidemia, osteoporosis, or hypertension. No biochemical abnormality in the GH/IGF1 axis or molecular defect was found. CONCLUSIONS: While the association of IUGR and adult MS, including diabetes, has been well documented, these subjects did not have typical manifestations of MS. Abnormalities in common components that could result in a combination of IUGR, severe postnatal growth, and insulin resistance have been ruled out. A mutation in an unidentified gene may affect intrauterine and postnatal growth, with insulin resistance directly affected or as a result of this growth phenomenon.
Assuntos
Consanguinidade , Diabetes Mellitus Tipo 1/genética , Retardo do Crescimento Fetal/genética , Transtornos do Crescimento/genética , Hormônio do Crescimento Humano/genética , Fator de Crescimento Insulin-Like I/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Feminino , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/diagnóstico , Fibroblastos/metabolismo , Transtornos do Crescimento/sangue , Transtornos do Crescimento/diagnóstico , Hormônio do Crescimento Humano/sangue , Humanos , Resistência à Insulina/fisiologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
The acid-labile subunit (ALS) protein is crucial for maintaining the integrity of the circulating IGF/IGFBP system. In humans, complete ALS deficiency is characterized by severely reduced serum IGF-I and IGFBP-3 concentrations that is incongruent with the associated mild growth retardation (height SDS -2 to -3 SDS before and during puberty). Twenty-one patients have been described with ALS deficiency, representing 16 unique homozygous or compound heterozygous inactivating mutations of the IGFALS gene. Pubertal delay in boys and insulin insensitivity are common findings. In the assessment of a child with short stature ALS deficiency should be consider in those patients presenting: 1) a normal response to GH stimulation test, 2) low IGF-I levels associated with more profoundly reduced IGFBP-3 levels, 3) a mild growth retardation, apparently out of proportion to the degree of IGF-I and IGFBP-3 deficits, 4) lack of response to an IGF generation test and 5) insulin insensitivity.
Assuntos
Glicoproteínas/deficiência , Adolescente , Animais , Proteínas de Transporte/genética , Criança , Feminino , Glicoproteínas/genética , Transtornos do Crescimento/fisiopatologia , Humanos , Resistência à Insulina/fisiologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/deficiência , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , CamundongosAssuntos
DNA/genética , Transtornos do Crescimento/etiologia , Pneumopatias/etiologia , Mutação , Fator de Transcrição STAT5/deficiência , Imunodeficiência Combinada Severa/etiologia , Animais , Predisposição Genética para Doença , Transtornos do Crescimento/genética , Transtornos do Crescimento/metabolismo , Humanos , Pneumopatias/genética , Pneumopatias/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/metabolismoRESUMO
The majority of insulin-like growth factor (IGF)-I and IGF-II circulate in the serum as a complex with the insulin-like growth factor binding protein (IGFBP)-3 or IGFBP-5, and an acid-labile subunit (ALS). The function of ALS is to prolong the half-life of the IGF-I-IGFBP-3/IGFBP-5 binary complexes. Fourteen different mutations of the human IGFALS gene have been identified in 17 patients, suggesting that ALS deficiency may be prevalent in a subset of patients with extraordinarily low serum levels of IGF-I and IGFBP-3 that remain abnormally low upon growth hormone stimulation. Postnatal growth was clearly affected. Commonly, the height standard deviation score before puberty was between -2 and -3, and approximately 1.4 SD shorter than the midparental height SDS. Pubertal delay was found in 50% of the patients. Circulating IGF-II, IGFBP-1, -2 and -3 levels were reduced, with the greatest reduction observed for IGFBP-3. Insulin insensitivity was a common finding, and some patients presented low bone mineral density. Human ALS deficiency represents a unique condition in which the lack of ALS proteins results in the disruption of the entire IGF circulating system. Despite a profound circulating IGF-I deficiency, there is only a mild impact on postnatal growth. The preserved expression of locally produced IGF-I might be responsible for the preservation of linear growth near normal limits.