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Nature Genetics Nov 2015We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of...
We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent in Sardinia (0.87% versus <0.01% elsewhere) and in the homozygous state causes Laron syndrome involving short stature. We find that this variant reduces height in heterozygotes by an average of 4.2 cm (-0.64 s.d.). The other variant, in the imprinted KCNQ1 gene (minor allele frequency (MAF) = 7.7% in Sardinia versus <1% elsewhere) reduces height by an average of 1.83 cm (-0.31 s.d.) when maternally inherited. Additionally, polygenic scores indicate that known height-decreasing alleles are at systematically higher frequencies in Sardinians than would be expected by genetic drift. The findings are consistent with selection for shorter stature in Sardinia and a suggestive human example of the proposed 'island effect' reducing the size of large mammals.
Topics: Adult; Aged; Aged, 80 and over; Body Height; Carrier Proteins; Female; Founder Effect; Gene Frequency; Genetic Variation; Genome-Wide Association Study; Genotype; Haplotypes; High-Throughput Nucleotide Sequencing; Humans; Islands; Italy; KCNQ1 Potassium Channel; Laron Syndrome; Longitudinal Studies; Male; Middle Aged; Selection, Genetic; Young Adult
PubMed: 26366551
DOI: 10.1038/ng.3403 -
European Journal of Endocrinology Sep 2015GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth...
CONTEXT AND OBJECTIVE
GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mild height reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations.
METHODS
We genotyped and performed clinical and laboratory evaluations in 52 relatives of two previously described Brazilian brothers with homozygous STAT5B c.424_427del mutation (21 heterozygous). Additionally, we obtained height data and genotype from 1104 adult control individuals from the same region in Brazil and identified five additional families harboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data from first-degree relatives of patients with homozygous STAT5B mutations (17 individuals from seven families). Data from heterozygous individuals and non-carriers were compared.
RESULTS
Individuals carrying heterozygous STAT5B c.424_427del mutation were 0.6 SDS shorter than their non-carrier relatives (P = 0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF1 (P = 0.028) and IGFBP3 (P = 0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygous STAT5B mutations had an average height SDS of -1.4 ± 0.8 when compared with population-matched controls (P < 0.001).
CONCLUSIONS
STAT5B mutations in the heterozygous state have a significant negative impact on height (∼ 3.9 cm). This effect is milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support the hypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability.
Topics: Adolescent; Adult; Body Height; Child; Eczema; Female; Heterozygote; Humans; Laron Syndrome; Lung Diseases, Interstitial; Male; Middle Aged; Mutation; Pedigree; STAT5 Transcription Factor; Young Adult
PubMed: 26034074
DOI: 10.1530/EJE-15-0398 -
The Journal of Clinical Endocrinology... Jul 2015Ecuadorian subjects with GH receptor deficiency (GHRD) have not developed diabetes, despite obesity.
CONTEXT
Ecuadorian subjects with GH receptor deficiency (GHRD) have not developed diabetes, despite obesity.
OBJECTIVE
We sought to determine the metabolic associations for this phenomenon.
DESIGN
Four studies were carried out: 1) glucose, lipid, adipocytokine concentrations; 2) metabolomics evaluation; 3) metabolic responses to a high-calorie meal; and 4) oral glucose tolerance tests.
SETTING
Clinical Research Institute in Quito, Ecuador.
SUBJECTS
Adults homozygous for the E180 splice mutation of the GH receptor (GHRD) were matched for age, gender, and body mass index with unaffected control relatives (C) as follows: study 1, 27 GHRD and 35 C; study 2, 10 GHRD and 10 C; study 3, seven GHRD and 11 C; and study 4, seven GHRD and seven C.
RESULTS
Although GHRD subjects had greater mean percentage body fat than controls, their fasting insulin, 2-hour blood glucose, and triglyceride levels were lower. The indicator of insulin sensitivity, homeostasis model of assessment 2%S, was greater (P < .0001), and the indicator of insulin resistance, homeostasis model of assessment 2-IR, was lower (P = .0025). Metabolomic differences between GHRD and control subjects were consistent with their differing insulin sensitivity, including postprandial decreases of branched-chain amino acids that were more pronounced in controls. High molecular weight and total adiponectin concentrations were greater in GHRD (P = .0004 and P = .0128, respectively), and leptin levels were lower (P = .02). Although approximately 65% the weight of controls, GHRD subjects consumed an identical high-calorie meal; nonetheless, their mean glucose concentrations were lower, with mean insulin levels one-third those of controls. Results of the 2-hour oral glucose tolerance test were similar.
MAIN OUTCOME MEASURES
Measures of insulin sensitivity, adipocytokines, and energy metabolites.
CONCLUSIONS
Without GH counter-regulation, GHRD is associated with insulin efficiency and obesity. Lower leptin levels, despite higher percentage body fat, suggest that obesity-associated leptin resistance is GH dependent. Elevated adiponectin levels not correlated with percentage body fat indicate that GH signaling is necessary for their typical suppression with obesity.
Topics: Adipokines; Adult; Body Mass Index; Carbohydrate Metabolism; Case-Control Studies; Ecuador; Female; Humans; Insulin Resistance; Laron Syndrome; Lipids; Male; Middle Aged; Obesity; Young Adult
PubMed: 25985182
DOI: 10.1210/jc.2015-1678 -
Hormone Research in Paediatrics 2015We report data from the EU Increlex® Growth Forum Database (IGFD) Registry, an ongoing, open-label, observational study monitoring clinical practice use of recombinant...
BACKGROUND/AIMS
We report data from the EU Increlex® Growth Forum Database (IGFD) Registry, an ongoing, open-label, observational study monitoring clinical practice use of recombinant human insulin-like growth factor-1 (rhIGF-1) therapy in children.
METHODS
Safety and effectiveness data on rhIGF-1 treatment of 195 enrolled children with growth failure were collected from December 2008 to September 2013.
RESULTS
Mean ± SD (95% CI) height velocity during first year of rhIGF-1 treatment was 6.9 ± 2.2 cm/year (6.5; 7.2) (n = 144); in prepubertal patients naïve to treatment, this was 7.3 ± 2.0 cm/year (6.8; 7.7) (n = 81). Female sex, younger age at start of rhIGF-1 therapy, and lower baseline height SDS predicted first-year change in height SDS. The most frequent targeted treatment-emergent adverse events (% patients) were hypoglycemia (17.6%, predictors: young age, diagnosis of Laron syndrome, but not rhIGF-1 dose), lipohypertrophy (10.6%), tonsillar hypertrophy (7.4%), injection site reactions (6.4%), and headache (5.9%). Sixty-one serious adverse events (37 related to rhIGF-1 therapy) were reported in 31 patients (16.5%).
CONCLUSION
Safety and effectiveness data on use of rhIGF-1 in a 'real-world' setting were similar to those from controlled randomized trials. Severe growth phenotype and early start of rhIGF-1 improved height response and predicted risk of hypoglycemia.
Topics: Adolescent; Child; Child, Preschool; Databases, Factual; Europe; Female; Growth Disorders; Humans; Insulin-Like Growth Factor I; Male; Recombinant Proteins
PubMed: 25824333
DOI: 10.1159/000371798 -
Indian Journal of Endocrinology and... Nov 2014Patients with growth hormone (GH) insensitivity (also known as Laron syndome) have been reported from the Mediterranean region and Southern Eucador, with few case...
INTRODUCTION
Patients with growth hormone (GH) insensitivity (also known as Laron syndome) have been reported from the Mediterranean region and Southern Eucador, with few case reports from India. We present here the clinical and endocrine profile of 9 children with Laron syndrome from India.
MATERIAL AND METHODS
Nine children diagnosed with Laron syndrome based on clinical features of GH deficiency and biochemical profile suggestive of GH resistance were studied over a period of 5 years from January 2008 to January 2013.
RESULTS AND DISCUSSION
Age of presentation was between 2.5-11.5 years. All children were considerably short on contemporary Indian charts with mean (SD) height Z score -5.2 (1.6). However, they were within ± 2 SD on Laron charts. No child was overweight [mean (SD) BMI Z score 0.92 (1.1)]. All children had characteristic facies of GH deficiency with an added feature of prominent eyes. Three boys had micropenis and 1 had unilateral undescended testis. All children had low IGF-1 (<5 percentile) and IGFP-3 (<0.1 percentile) with high basal and stimulated GH [Basal GH mean (SD) = 13.78 (12.75) ng/ml, 1-h stimulated GH mean (SD) = 46.29 (25.68) ng/ml]. All children showed poor response to IGF generation test.
CONCLUSION
Laron syndrome should be suspected in children with clinical features of GH deficiency, high GH levels and low IGF-1/IGFBP-3. These children are in a state of GH resistance and need IGF-1 therapy.
PubMed: 25364685
DOI: 10.4103/2230-8210.140236 -
Proceedings of the National Academy of... Aug 2014The original centrally defining features of "Homo floresiensis" are based on bones represented only in the single specimen LB1. Initial published values of 380-mL...
The original centrally defining features of "Homo floresiensis" are based on bones represented only in the single specimen LB1. Initial published values of 380-mL endocranial volume and 1.06-m stature are markedly lower than later attempts to confirm them, and facial asymmetry originally unreported, then denied, has been established by our group and later confirmed independently. Of nearly 200 syndromes in which microcephaly is one sign, more than half include asymmetry as another sign and more than one-fourth also explicitly include short stature. The original diagnosis of the putative new species noted and dismissed just three developmental abnormalities. Subsequent independent attempts at diagnosis (Laron Syndrome, Majewski osteodysplastic primordial dwarfism type II, cretinism) have been hampered a priori by selectively restricted access to specimens, and disparaged a posteriori using data previously unpublished, without acknowledging that all of the independent diagnoses corroborate the patent abnormal singularity of LB1. In this report we establish in detail that even in the absence of a particular syndromic diagnosis, the originally defining features of LB1 do not establish either the uniqueness or normality necessary to meet the formal criteria for a type specimen of a new species. In a companion paper we present a new syndromic diagnosis for LB1.
Topics: Animals; Bone and Bones; Fossils; Hominidae; Indonesia; Phylogeny; Probability
PubMed: 25092307
DOI: 10.1073/pnas.1407385111 -
Matrix Biology : Journal of the... Feb 2014The growth hormone/insulin-like growth factor-I (GH/IGF-I) axis is an important stimulator of collagen synthesis in connective tissue, but the effect of chronically...
The growth hormone/insulin-like growth factor-I (GH/IGF-I) axis is an important stimulator of collagen synthesis in connective tissue, but the effect of chronically altered GH/IGF-I levels on connective tissue of the muscle-tendon unit is not known. We studied three groups of mice; 1) giant transgenic mice that expressed bovine GH (bGH) and had high circulating levels of GH and IGF-I, 2) dwarf mice with a disrupted GH receptor gene (GHR-/-) leading to GH resistance and low circulating IGF-I, and 3) a wild-type control group (CTRL). We measured the ultra-structure, collagen content and mRNA expression (targets: GAPDH, RPLP0, IGF-IEa, IGF-IR, COL1A1, COL3A1, TGF-β1, TGF-β2, TGF-β3, versican, scleraxis, tenascin C, fibronectin, fibromodulin, decorin) in the Achilles tendon, and the mRNA expression was also measured in calf muscle (same targets as tendon plus IGF-IEb, IGF-IEc). We found that GHR-/- mice had significantly lower collagen fibril volume fraction in Achilles tendon, as well as decreased mRNA expression of IGF-I isoforms and collagen types I and III in muscle compared to CTRL. In contrast, the mRNA expression of IGF-I isoforms and collagens in bGH mice was generally high in both tendon and muscle compared to CTRL. Mean collagen fibril diameter was significantly decreased with both high and low GH/IGF-I signaling, but the GHR-/- mouse tendons were most severely affected with a total loss of the normal bimodal diameter distribution. In conclusion, chronic manipulation of the GH/IGF-I axis influenced both morphology and mRNA levels of selected genes in the muscle-tendon unit of mice. Whereas only moderate structural changes were observed with up-regulation of GH/IGF-I axis, disruption of the GH receptor had pronounced effects upon tendon ultra-structure.
Topics: Animals; Cattle; Collagen Type I; Connective Tissue; Growth Hormone; Insulin-Like Growth Factor I; Mice; Mice, Transgenic; Muscle, Skeletal; Protein Biosynthesis; RNA, Messenger; Tendons
PubMed: 24080228
DOI: 10.1016/j.matbio.2013.09.005 -
PloS One 2013The origin of hominins found on the remote Indonesian island of Flores remains highly contentious. These specimens may represent a new hominin species, Homo... (Comparative Study)
Comparative Study
The origin of hominins found on the remote Indonesian island of Flores remains highly contentious. These specimens may represent a new hominin species, Homo floresiensis, descended from a local population of Homo erectus or from an earlier (pre-H. erectus) migration of a small-bodied and small-brained hominin out of Africa. Alternatively, some workers suggest that some or all of the specimens recovered from Liang Bua are pathological members of a small-bodied modern human population. Pathological conditions proposed to explain their documented anatomical features include microcephaly, myxoedematous endemic hypothyroidism ("cretinism") and Laron syndrome (primary growth hormone insensitivity). This study evaluates evolutionary and pathological hypotheses through comparative analysis of cranial morphology. Geometric morphometric analyses of landmark data show that the sole Flores cranium (LB1) is clearly distinct from healthy modern humans and from those exhibiting hypothyroidism and Laron syndrome. Modern human microcephalic specimens converge, to some extent, on crania of extinct species of Homo. However in the features that distinguish these two groups, LB1 consistently groups with fossil hominins and is most similar to H. erectus. Our study provides further support for recognizing the Flores hominins as a distinct species, H. floresiensis, whose affinities lie with archaic Homo.
Topics: Animals; Autopsy; Body Weights and Measures; Bone and Bones; Fossils; Hominidae; Humans; Hypothyroidism; Indonesia; Islands; Laron Syndrome; Microcephaly; Principal Component Analysis; Skull
PubMed: 23874886
DOI: 10.1371/journal.pone.0069119 -
Journal of Bone and Mineral Research :... Jul 2013States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and...
States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout [GHRKO]) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT mouse model. In GHRKO-HIT mice, serum IGF-1 levels were restored via transgenic expression of Igf-1, allowing us to study how endocrine IGF-1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH-resistant state, normalization of serum IGF-1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF-1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf-1 gene expression, blunted GH-mediated effects on the skeleton that are independent of serum or tissue IGF-1, and poor delivery of IGF-1 to the tissues. These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron syndrome does not achieve full skeletal growth.
Topics: Animals; Bone Development; Bone and Bones; Disease Models, Animal; Female; Hormone Replacement Therapy; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Male; Mice; Mice, Mutant Strains; Receptors, Somatotropin; Transgenes
PubMed: 23456957
DOI: 10.1002/jbmr.1920 -
Journal of Translational Medicine Nov 2012Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple... (Review)
Review
Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions). IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range.
Topics: Animals; Disease; Growth and Development; Humans; Insulin-Like Growth Factor I; Organ Specificity
PubMed: 23148873
DOI: 10.1186/1479-5876-10-224