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Immunoassays are widely used for measuring gonadotropins, including luteinizing hormone (LH), as these are both specific and sensitive. Because LH is microheterogeneous it has been claimed that the specificity of monoclonal antibodies used in two-site immunoassays can limit their clinical utility. Furthermore, we reported earlier a common genetic variant form of LH due to amino acid alterations in the LHbeta gene that is poorly or not recognized by antibodies directed against epitopes present in the intact molecule. We here report the result of an LH epitope mapping using 30 different monoclonal antibodies. The antigenic area affected by the amino acid alterations is fairly large, as antibodies to the two intact domains are able to sandwich each other. Combinations of alpha-beta or beta-beta antibodies generally provide alternatives for unbiased detection of circulating LH and some have reasonably good discrimination of human chorionic gonadotropin. The beta-beta combinations exhibit a peculiarity in urine determinations as they detect the urinary beta-core fragment. Our aims were to study the altered immunoreactivity caused by the amino acid changes and to design two-site LH assays fully capable of recognizing the biologically active LH variant. We also conclude that the variability in recognizing the universally occurring LH variant is the most important factor contributing to the widely documented LH immunoassay discrepancies.
Department of BioMedical Research, University of Bern, Bern, Switzerland
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Department of BioMedical Research, University of Bern, Bern, Switzerland
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
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Department of BioMedical Research, University of Bern, Bern, Switzerland
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Department of BioMedical Research, University of Bern, Bern, Switzerland
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Biallelic variants of steroidogenic acute regulatory protein (STAR/STARD1) may cause primary adrenal insufficiency and 46,XY disorder of sex development. STAR plays a pivotal role in transporting cholesterol into mitochondria where cholesterol serves as an essential substrate for initiating steroid biosynthesis by its conversion to pregnenolone. Generally, loss-of-function mutations of STAR cause the classic form of lipoid congenital adrenal hyperplasia (LCAH) where steroidogenesis of the adrenal cortex and the gonads is severely affected. By contrast, partial activity of STAR causes a less severe phenotype, the non-classic LCAH, which is characterized by later onset and initial manifestation with isolated adrenal insufficiency only. Disease-causing STAR variants are very rare. Numerous variants of all types have been described worldwide. Prevailing variants have been reported from Japan and Korea and in some population clusters where STAR is more common. Genotype–phenotype correlation is pretty good for STAR variants. While the exact mechanisms of cholesterol transport into mitochondria for steroidogenesis are still under investigation, the important role of STAR in this process is evident by inactivating STAR variants causing LCAH. The mechanism of disease with STAR deficiency is best described by a two-hit model: the first hit relates to impaired cholesterol import into mitochondria and thus lack of substrate for all steroid hormone biosynthesis; the second hit then relates to massive cytoplasmic lipid overload (evidenced by typically enlarged and fatty adrenal glands) leading to cell death and organ destruction. This review summarizes phenotype and genotype characteristics of human STAR variants found through the ClinVar database.
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Faculty of Natural Sciences and Technology, Åbo Akademi University, Turku, Finland
Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland
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Department of Surgery and Cancer, Institute of Reproductive and Developmental Biology, Hammersmith Campus, Imperial College London, London, UK
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Glycoprotein hormones are complex hormonally active macromolecules. Luteinizing hormone (LH) is essential for the postnatal development and maturation of the male gonad. Inactivating Luteinizing hormone beta (LHB) gene mutations are exceptionally rare and lead to hypogonadism that is particularly severe in males. We describe a family with selective LH deficiency and hypogonadism in two brothers. DNA sequencing of LHB was performed and the effects of genetic variants on hormone function and secretion were characterized by mutagenesis studies, confocal microscopy and functional assays. A 20-year-old male from a consanguineous family had pubertal delay, hypogonadism and undetectable LH. A homozygous c.118_120del (p.Lys40del) mutation was identified in the patient and his brother, who subsequently had the same phenotype. Treatment with hCG led to pubertal development, increased circulating testosterone and spermatogenesis. Experiments in HeLa cells revealed that the mutant LH is retained intracellularly and showed diffuse cytoplasmic distribution. The mutated LHB heterodimerizes with the common alpha-subunit and can activate its receptor. Deletion of flanking glutamic acid residues at positions 39 and 41 impair LH to a similar extent as deletion of Lys40. This region is functionally important across all heterodimeric glycoprotein hormones, because deletion of the corresponding residues in hCG, follicle-stimulating hormone and thyroid-stimulating hormone beta-subunits also led to intracellular hormone retention. This novel LHB mutation results in hypogonadism due to intracellular sequestration of the hormone and reveals a discrete region in the protein that is crucial for normal secretion of all human glycoprotein hormones.
South Australian Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, Australia
Adelaide Medical School, University of Adelaide, Adelaide, Australia
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Garvan Institute of Medical Research, Sydney, NSW, Australia
St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia
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St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia
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Academy for Medical Education, Faculty of Medicine, the University of Queensland, Brisbane, Australia
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Garvan Institute of Medical Research, Sydney, NSW, Australia
St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia
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‘Pituitary tumours’ is an umbrella term for various tumours originating from different regions of the hypothalamic–pituitary system. The vast majority of pituitary tumours are pituitary adenomas, also recently referred to as pituitary neuroendocrine tumours. The prevalence of clinically relevant pituitary adenomas is approximately 1 in 1000; other pituitary tumours such as craniopharyngioma and pituicytoma are comparatively very rare. This review addresses the molecular and genetic aspects of pituitary adenomas. We first discuss the germline genetic variants underlying familial pituitary tumours, which account for approximately 5% of all pituitary adenoma cases. This includes variants in established pituitary adenoma/hyperplasia predisposition genes (MEN1, PRKAR1A, AIP, CDKN1B, GPR101, SDHA, SDHB, SDHC, SDHD, SDHAF2) as well as emerging genetic associations. In addition, we discuss McCune–Albright syndrome which lies between the germline and somatic pituitary tumour genes as the causative GNAS mutations are postzygotic rather than being inherited, and the condition is associated with multiglandular features due to the involvement of different cell lines rather than being limited to the pituitary. By contrast, somatic GNAS mutations contribute to sporadic acromegaly. USP8 is the only other gene where somatic driver mutations have been established in sporadic pituitary tumorigenesis. However, there are now known to be a variety of other somatic genetic and molecular changes underpinning sporadic pituitary adenomas which we review here, namely: copy number variation, molecular changes in signalling and hypoxia pathways, epithelial–mesenchymal transition, DNA repair, senescence, the immune microenvironment and epigenetics.
Department of Physiology and Biophysics, Institute of Bioinformatics and Systems Biology, Qatar Foundation – Education City, Weill Cornell Medical College – Qatar, PO Box 24144, Doha, Qatar
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phenotype as a function of genotype (reviewed in Suhre & Gieger (2012) ). These so-called genetically influenced metabotypes (GIMs) are generally constituted of relatively frequent genetic variants, with minor allele frequencies of 20% and above, show large
Department of Nutrition, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
Nutrition Research Institute, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
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Bond Life Sciences Center, University of Missouri, Columbia, Missouri, USA
Thompson Center for Autism and Neurobehavioral Disorders, University of Missouri, Columbia, Missouri, USA
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Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina, USA
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Center for Human Health and the Environment, North Carolina State University, Raleigh, North Carolina, USA
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/L ( Holick et al. 2011 ) and represents one of the most widespread but treatable nutrient deficiencies ( Holick et al. 2011 ). VDD has been attributed to dietary depletion, insufficient sunlight exposure, adiposity and genetic variants ( Ross 2011
Department of Endocrinology and Diabetes, Monash Health, Victoria, Australia
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Department of Endocrinology and Diabetes, Monash Health, Victoria, Australia
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Department of Endocrinology and Diabetes, Monash Health, Victoria, Australia
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many other chronic diseases such as type 2 diabetes mellitus, the genetic cause of PCOS is likely polygenic due to the cumulative effect of many genetic variants without a clear pattern of inheritance ( Lunde et al. 1989 , Dapas & Dunaif 2022 ). The
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human nodular goitres, it has been demonstrated that E 2 stimulated the growth of thyroid cells derived from female and male glands to the same extent ( Manole et al . 2001 ). In line with this finding, no common genetic variants in sex hormone pathway
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addition, sexual dimorphism for specific genetic variants in metabolism-related genes was described. This work laid basis for monitoring in personalized medicine differentiating, e.g. amino acid or lipid metabolism in woman and man. The findings were of
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) ( Fig. 2 ). Recently, FABP4 plasma levels have been associated with elevated CVD mortality in men with type 2 diabetes mellitus ( Liu et al . 2016 ). Decreased FABP4 expression as a consequence of a genetic variant of the FABP4 promoter (T-87C) results
