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1.
Hum Mutat ; 40(11): 2033-2043, 2019 11.
Article in English | MEDLINE | ID: mdl-31231873

ABSTRACT

Isolated growth hormone deficiency (IGHD) is a rare condition mainly caused by mutations in GH1. The aim of this study was to assess the contribution of GHRHR mutations to IGHD in an unusually large group of patients. All GHRHR coding exons and flanking intronic regions were sequenced in 312 unrelated patients with nonsyndromic IGHD. Functional consequences of all newly identified missense variants were assessed in vitro (i.e., study of the expression of recombinant GHRHRs and their ability to activate the cyclic adenosine monophosphate (cAMP) signaling pathway). Genotype-phenotype correlation analyses were performed according to the nature of the identified mutation. We identified 20 different disease-causing GHRHR mutations (truncating and missense loss-of-function mutations), among which 15 are novel, in 24 unrelated patients. Of note, about half (13/24) of those patients represent sporadic cases. The clinical phenotype of patients with at least one missense GHRHR mutation was found to be indistinguishable from that of patients with bi-allelic truncating mutations. This study, which unveils disease-causing GHRHR mutations in 8% (24/312) of IGHD cases, identifies GHRHR as the second IGHD gene most frequently involved after GH1. The finding that 8% of IGHD cases without GH1 mutations are explained by GHRHR molecular defects (including missense mutations), together with the high proportion of sporadic cases among those patients, has important implications for genetic counseling.


Subject(s)
Dwarfism, Pituitary/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Mutation , Receptors, Neuropeptide/genetics , Receptors, Pituitary Hormone-Regulating Hormone/genetics , Alleles , Amino Acid Sequence , Amino Acid Substitution , Cyclic AMP , DNA Mutational Analysis , Dwarfism, Pituitary/diagnosis , Female , Genotype , Human Growth Hormone/genetics , Humans , Male , Pedigree , Receptors, Neuropeptide/chemistry , Receptors, Pituitary Hormone-Regulating Hormone/chemistry
2.
J Clin Endocrinol Metab ; 95(3): 1463-8, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20097706

ABSTRACT

CONTEXT: Human lipodystrophies are characterized by loss of adipose tissue, insulin resistance, and metabolic complications. The mechanisms linking fat loss to severe insulin resistance remain unclear. Adipokines may have important roles as intermediary players in metabolism. OBJECTIVE: We sought to determine the plasma concentrations of leptin and adiponectin in patients with Berardinelli-Seip congenital lipodystrophy (BSCL) harboring mutations in the genes encoding either 1-acylglycerol-3-phosphate-O-acyltransferase-2 (AGPAT2) or BSCL2/seipin, in comparison with patients with other forms of inherited or acquired lipodystrophies or insulin receptor alterations. DESIGN: Leptin and total and high-molecular-weight adiponectin were measured in plasma of 16 BSCL1/AGPAT2 and 19 BSCL2/seipin patients and compared with heterozygous (n = 22) or nonmutated relatives (controls, n = 30); patients with Dunnigan-type partial lipodystrophy due to lamin A/C mutations (n = 23), HIV-related lipodystrophy (n = 124), and insulin receptor dysfunctions caused by mutations or autoantibodies (n = 17). RESULTS: Leptin was dramatically decreased in BSCL patients as compared with other subgroups. Adiponectin was decreased in BSCL as compared with controls and patients with altered insulin receptor but was discrepant between the two BSCL subgroups. Whereas total and high-molecular-weight adiponectin levels were almost undetectable in BSCL1/AGPAT2 patients, higher levels were detected in BSCL2/seipin patients, comparable with those of patients with partial lipodystrophy. Adiponectin greater than 1.6 mg/liter had a 100% negative predictive value for AGPAT2 mutations in inherited lipodystrophies. CONCLUSIONS: The presence of circulating adiponectin in BSCL2/seipin patients with near absence of adipose tissue outlines the complexity of adiponectin biology. Use of circulating adiponectin might be helpful to guide the genetic investigations in BSCL.


Subject(s)
1-Acylglycerol-3-Phosphate O-Acyltransferase/deficiency , Adiponectin/blood , GTP-Binding Protein gamma Subunits/deficiency , Lipodystrophy, Congenital Generalized/blood , Adolescent , Analysis of Variance , Child , Child, Preschool , Enzyme-Linked Immunosorbent Assay , Female , Humans , Leptin/blood , Lipodystrophy, Congenital Generalized/genetics , Male , Statistics, Nonparametric
3.
Biochimie ; 91(6): 796-803, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19278620

ABSTRACT

Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare recessive disease characterized by near absence of adipose tissue and severe insulin resistance. In most cases, BSCL is due to loss-of-function mutations in the genes encoding either seipin of unknown function or 1-acyl-glycerol-3-phosphate O-acyltransferase 2 (AGPAT2) which catalyses the formation of phosphatidic acid from lysophosphatidic acid. We studied the lipid profile of lymphoblastoid cell-lines from 20 BSCL patients with null mutations in the genes encoding either seipin (n=12) or AGPAT2 (n=8) in comparison to nine control cell-lines. In seipin deficient cells, we observed alterations in the pattern of lipid droplets which were decreased in size and increased in number as compared to control cells. We also observed alterations in the triglycerides content as well as in the fatty acid composition from triglycerides and phosphatidylethanolamine, with an increased proportion of saturated fatty acids at the expense of the corresponding monounsaturated fatty acids, reflecting a defect in Delta9-desaturase activity. In AGPAT2 deficient cells, no specific alterations in lipid droplet pattern nor in fatty acid composition was observed but the cellular level of lysophosphatidic acid was increased as compared to that of control and seipin deficient cells. These results indicate that seipin like AGPAT2 is involved in lipid metabolism but exerts a different function. Seipin intervenes at a proximal step in triglycerides and phospholipids biosynthesis being involved in the pathway that links fatty acid Delta9 desaturation to lipid droplet formation. These findings provide new insights into how seipin deficiency causes severe lipodystrophy.


Subject(s)
Fatty Acids, Unsaturated/metabolism , GTP-Binding Protein gamma Subunits/deficiency , Lipid Metabolism , Lipodystrophy, Congenital Generalized/pathology , Mutation , 1-Acylglycerol-3-Phosphate O-Acyltransferase/genetics , 1-Acylglycerol-3-Phosphate O-Acyltransferase/metabolism , Adolescent , Adult , Cell Line, Transformed , Child , Child, Preschool , Fatty Acids, Unsaturated/chemistry , Female , GTP-Binding Protein gamma Subunits/genetics , GTP-Binding Protein gamma Subunits/metabolism , Humans , Infant , Lipids/analysis , Lipids/chemistry , Lipodystrophy, Congenital Generalized/genetics , Lipodystrophy, Congenital Generalized/metabolism , Lymphocytes/cytology , Lymphocytes/metabolism , Lymphocytes/ultrastructure , Male , Microscopy, Confocal , Microscopy, Electron , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Stearoyl-CoA Desaturase/metabolism , Triglycerides/metabolism , Young Adult
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