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Open AccessEditorial

Special Issue “Genetics and Epigenetics in Endocrine Disorders”

by Katarina Trebušak Podkrajšek and Primož Kotnik

Genes 2023, 14(9), 1763; https://doi.org/10.3390/genes14091763 - 05 Sep 2023

Viewed by 693

Abstract

In the last decade, the development of high-throughput sequencing methodologies has significantly improved the gathering of genomic information and consequent under-standing of the genetic and epigenetic background of complex and monogenetic endocrine disorders [...] Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)

Research

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10 pages, 2663 KiB

Open AccessArticle

Expression Profiling of Pdx1, Ngn3, and MafA in the Liver and Pancreas of Recovering Streptozotocin-Induced Diabetic Rats

by Amani M. Al-Adsani, Anoud N. Al-Otaibi, Sahar A. Barhoush, Khaled K. Al-Qattan and Suzanne A. Al-Bustan

Genes 2022, 13(9), 1625; https://doi.org/10.3390/genes13091625 - 10 Sep 2022

Cited by 5 | Viewed by 2166

Abstract

Studies in animal diabetic models have demonstrated the possibility of islet regeneration through treatment with natural extracts, such as Allium sativum (garlic). This study aimed to investigate the effect of garlic extract (GE) on the expression of three genes (Ngn3, Pdx1 [...] Read more.

Studies in animal diabetic models have demonstrated the possibility of islet regeneration through treatment with natural extracts, such as Allium sativum (garlic). This study aimed to investigate the effect of garlic extract (GE) on the expression of three genes (Ngn3, Pdx1, and MafA) in the pancreas and liver of diabetic rats. Thirty-two rats were divided into two groups, streptozotocin (STZ)-induced diabetic rats (n = 16) and healthy rats (n = 16). Both groups were subdivided into GE-treated (n = 8), and those administered 0.9% normal saline (NS) (n = 8) for 1 week (n = 4) and 8 weeks (n = 4). In the pancreas of diabetic rats treated with GE for 1 week, all three genes, Ngn3, Pdx1, and MafA, were significantly upregulated (p ≤ 0.01, p ≤ 0.05, and p ≤ 0.001, respectively) when compared to diabetic rats treated with NS only. However, after eight weeks of GE treatment, the expression of all three genes decreased as blood insulin increased. In the liver, only Pdx1 expression significantly (p ≤ 0.05) increased after 8 weeks. The significant expression of Ngn3, Pdx1, and MafA in the pancreas by week 1 may have induced the maturation of juvenile β-cells, which escaped the effects of STZ and caused an increase in serum insulin. Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)

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15 pages, 1063 KiB

Open AccessArticle

Interactome of PTH-Regulated miRNAs and Their Predicted Target Genes for Investigating the Epigenetic Effects of PTH (1–34) in Bone Metabolism

by Lucija Ana Vrščaj, Janja Marc and Barbara Ostanek

Genes 2022, 13(8), 1443; https://doi.org/10.3390/genes13081443 - 13 Aug 2022

Cited by 2 | Viewed by 1968

Abstract

Osteoporosis is a metabolic bone disease that mostly affects the elderly. A lot of drugs are available, mostly with an antiresorptive effect but just a few with an osteoanabolic effect, meaning they promote bone building. PTH (1-34) or teriparatide is an osteoanabolic drug, [...] Read more.

Osteoporosis is a metabolic bone disease that mostly affects the elderly. A lot of drugs are available, mostly with an antiresorptive effect but just a few with an osteoanabolic effect, meaning they promote bone building. PTH (1-34) or teriparatide is an osteoanabolic drug, but its efficacy varies between individuals. We performed a literature review and extracted a dataset of 62 microRNAs (miRNAs) from 10 different studies; predicted miRNA target interactions (MTIs) were obtained with the help of four software tools: DIANA, miRWalk, miRDB and TargetScan. With the construction of an interactome of PTH-regulated miRNAs and their predicted target genes, we elucidated miR-146a-5p, miR-551b-5p, miR-205-3p, miR-33a-3p, miR-338-5p as miRNAs with the most interactions and miR-410-3p as the miRNA targeting bone-related pathways with the highest significance. These miRNAs could help in further understanding the mechanism of action of PTH on bone metabolism and osteoporosis. They also have the potential for novel network-based biomarkers for osteoporosis treatment efficacy and safety and as new therapeutic targets. Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)

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12 pages, 1706 KiB

Open AccessArticle

Long-Term Follow-Up of Three Family Members with a Novel NNT Pathogenic Variant Causing Primary Adrenal Insufficiency

by Tjasa Krasovec, Jaka Sikonja, Mojca Zerjav Tansek, Marusa Debeljak, Sasa Ilovar, Katarina Trebusak Podkrajsek, Sara Bertok, Tine Tesovnik, Jernej Kovac, Jasna Suput Omladic, Michaela F. Hartmann, Stefan A. Wudy, Magdalena Avbelj Stefanija, Tadej Battelino, Primoz Kotnik and Urh Groselj

Genes 2022, 13(5), 717; https://doi.org/10.3390/genes13050717 - 20 Apr 2022

Cited by 6 | Viewed by 2298

Abstract

Nicotinamide nucleotide transhydrogenase (NNT) deficiency causes primary adrenal insufficiency (PAI) and possibly some extra-adrenal manifestations. A limited number of these patients were previously described. We present the clinical and genetic characteristics of three family members with a biallelic novel pathogenic variant in the [...] Read more.

Nicotinamide nucleotide transhydrogenase (NNT) deficiency causes primary adrenal insufficiency (PAI) and possibly some extra-adrenal manifestations. A limited number of these patients were previously described. We present the clinical and genetic characteristics of three family members with a biallelic novel pathogenic variant in the NNT gene. The patients were followed until the ages of 21.6, 20.2, and 4.2 years. PAI was diagnosed in the eldest two brothers after an Addisonian crisis and the third was diagnosed at the age of 4.5 months in the asymptomatic stage due to the genetic screening of family members. Whole exome sequencing with a targeted interpretation of variants in genes related to PAI was performed in all the patients. The urinary steroid metabolome was determined by gas chromatography–mass spectrometry in the asymptomatic patient. The three patients, who were homozygous for c.1575dup in the NNT gene, developed isolated glucocorticoid deficiency. The urinary steroid metabolome showed normal excretion of cortisol metabolites. The adolescent patients had slow pubertal progression with low–normal testicular volume, while testicular endocrine function was normal. Bone mineral density was in the range for osteopenia in both grown-up siblings. Echocardiography revealed no structural or functional heart abnormalities. This article is among the first with a comprehensive and chronologically-detailed description of patients with NNT deficiency. Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)

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14 pages, 2492 KiB

Open AccessArticle

A Novel Splice-Site Deletion in the POU1F1 Gene Causes Combined Pituitary Hormone Deficiency in Multiple Sudanese Pedigrees

by Samar S. Hassan, Mohamed Abdullah, Katarina Trebusak Podkrajsek, Salwa Musa, Areej Ibrahim, Omer Babiker, Jernej Kovac, Tadej Battelino and Magdalena Avbelj Stefanija

Genes 2022, 13(4), 657; https://doi.org/10.3390/genes13040657 - 08 Apr 2022

Cited by 2 | Viewed by 1913

Abstract

Pathogenic variants within the gene encoding the pituitary-specific transcription factor, POU class 1 homeobox 1 (POU1F1), are associated with combined pituitary hormone deficiency (CPHD), including growth hormone, prolactin, and thyrotropin stimulating hormone deficiencies. The aim of the study was to identify [...] Read more.

Pathogenic variants within the gene encoding the pituitary-specific transcription factor, POU class 1 homeobox 1 (POU1F1), are associated with combined pituitary hormone deficiency (CPHD), including growth hormone, prolactin, and thyrotropin stimulating hormone deficiencies. The aim of the study was to identify genetic aetiology in 10 subjects with CPHD from four consanguineous Sudanese families. Medical history, as well as hormonal and radiological information, was obtained from participants’ medical records. Targeted genetic analysis of the POU1F1 gene was performed in two pedigrees with a typical combination of pituitary deficiencies, using Sanger sequencing, and whole-exome sequencing was performed in the other two pedigrees, where hypocortisolism and additional neurologic phenotypes were also initially diagnosed. In POU1F1 gene (NM_001122757.2) a novel homozygous splice-site deletion—namely, c.744-5_749del—was identified in all 10 tested affected family members as a cause of CPHD. Apart from typical pituitary hormonal deficiencies, most patients had delayed but spontaneous puberty; however, one female had precocious puberty. Severe post-meningitis neurologic impairment was observed in three patients, of whom two siblings had Dyke–Davidoff–Masson syndrome, and an additional distantly related patient suffered from cerebral infarction. Our report adds to the previously reported POU1F1 gene variants causing CPHD and emphasises the importance of genetic testing in countries with high rates of consanguineous marriage such as Sudan. Genetic diagnostics elucidated that the aetiologies of hypopituitarism and brain abnormalities, identified in a subset of affected members, were separate. Additionally, as central hypocortisolism is not characteristic of POU1F1 deficiency, hydrocortisone replacement therapy could be discontinued. Elucidation of a genetic cause, therefore, contributed to the more rational clinical management of hypopituitarism in affected family members. Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)

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9 pages, 246 KiB

Open AccessArticle

Association of Long Non-Coding RNA Growth Arrest-Specific 5 Genetic Variants with Diabetic Retinopathy

by Chee-Ming Lee, Yi-Sun Yang, Edy Kornelius, Chien-Ning Huang, Min-Yen Hsu, Chia-Yi Lee, Shu-Yen Peng and Shun-Fa Yang

Genes 2022, 13(4), 584; https://doi.org/10.3390/genes13040584 - 25 Mar 2022

Cited by 6 | Viewed by 1811

Abstract

The aim of this work was to appraise the potential associations of single nucleotide polymorphisms (SNPs) of long non-coding RNA growth arrest-specific 5 (GAS5) with diabetic retinopathy (DR) in a diabetes mellitus (DM) population. Two loci of the GAS5 SNPs (rs55829688 [...] Read more.

The aim of this work was to appraise the potential associations of single nucleotide polymorphisms (SNPs) of long non-coding RNA growth arrest-specific 5 (GAS5) with diabetic retinopathy (DR) in a diabetes mellitus (DM) population. Two loci of the GAS5 SNPs (rs55829688 and rs145204276) were genotyped via TaqMan allelic discrimination in 449 non-DR patients and 273 DR subjects. The SNP rs145204276 Del/Del showed a significantly higher distribution in the DR group compared to the non-DR group (AOR: 2.487, 95% CI: 1.424–4.344, p = 0.001). During subgroup analyses, the non-proliferative diabetic retinopathy (NPDR) subgroup demonstrated a significantly higher ratio of the SNP rs145204276 Del/Del (AOR: 2.917, 95% CI: 1.574–5.406, p = 0.001) and Ins/Del + Del/Del (AOR: 1.242, 95% CI: 1.016–1.519, p = 0.034) compared to the non-DR population, while the proliferative diabetic retinopathy (PDR) subgroup did not reveal significant differences in either SNP rs145204276 or rs55829688 distributions compared to the non-DR group. Furthermore, patients with a GAS5 SNP rs145204276 Del/Del showed a significantly shorter DM duration than the wild type (Ins/Ins) (p = 0.021). In conclusion, our findings demonstrate that the GAS5 SNP rs145204276 Del/Del variant is associated with an increased susceptibility to DR in DM patients, particularly in those patients with NPDR. Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)

9 pages, 478 KiB

Open AccessArticle

APOE Polymorphism and Endocrine Functions in Subjects with Morbid Obesity Undergoing Bariatric Surgery

by Per G. Farup, Aina Jansen, Knut Hestad, Jan O. Aaseth and Helge Rootwelt

Genes 2022, 13(2), 222; https://doi.org/10.3390/genes13020222 - 25 Jan 2022

Cited by 4 | Viewed by 2436

Abstract

Background: Obesity is an interplay between genes and the environment, including lifestyle. The genetics of obesity is insufficiently understood. Apolipoprotein E (APOE) genetic polymorphism has been associated with a wide range of disorders. Knowing that some APOE alleles are associated with [...] Read more.

Background: Obesity is an interplay between genes and the environment, including lifestyle. The genetics of obesity is insufficiently understood. Apolipoprotein E (APOE) genetic polymorphism has been associated with a wide range of disorders. Knowing that some APOE alleles are associated with obesity and endocrine disorders that are common in obesity, the present study aimed at exploring associations between APOE polymorphisms and endocrine functions in subjects with obesity undergoing bariatric surgery. Methods: Analyses of hormones in blood collected before and one year after bariatric surgery were examined. The APOE alleles were grouped as follows: E2 = ε2ε2 + ε2ε3; E3 = ε3ε3 + ε2ε4; E4 = ε3ε4 + ε4ε4. The APOE groups were analysed as nominal and ordered groups (E2-E3-E4) with a linear mixed model to predict the hormonal effects of the groups. Results: Forty-nine women (79%) and thirteen (21%) men with a mean age of 47.7 (SD 8.5) years were included in the study. The adiponectin level was significantly lower (p < 0.05) in the E2 group compared with the E4 group. Adiponectin and cortisol were positively and negatively associated, respectively, with the ordered APOE groups. Conclusions: The ordered APOE groups E2-E3-E4 were significantly associated with high and low levels of adiponectin and cortisol, respectively. The findings indicate APOE-mediated effects on body weight and metabolic functions in subjects with morbid obesity. Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)

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7 pages, 238 KiB

Open AccessArticle

Detection of Del/Dup Inside SHOX/PAR1 Region in Children and Young Adults with Idiopathic Short Stature

by Jera Stritar, Lana Stavber, Maja Ficko, Primož Kotnik, Tadej Battelino, Katarina Trebušak Podkrajšek and Tinka Hovnik

Genes 2021, 12(10), 1546; https://doi.org/10.3390/genes12101546 - 29 Sep 2021

Cited by 2 | Viewed by 2113

Abstract

Short stature is a common growth disorder defined as a body height two standard deviations (SD) or more below the mean for a given age, gender, and population. A large part of the cases remains unexplained and is referred to as having idiopathic [...] Read more.

Short stature is a common growth disorder defined as a body height two standard deviations (SD) or more below the mean for a given age, gender, and population. A large part of the cases remains unexplained and is referred to as having idiopathic short stature (ISS). One of the leading genetic causes of short stature is variants of short stature homeobox-containing gene (SHOX) and is considered to be responsible for 2–15% of ISS. We aimed to analyse the regulatory and coding region of SHOX in Slovenian children and young adults with ISS and to investigate the pathogenicity of detected variants. Our cohort included 75 children and young adults with ISS. Multiplex ligation-dependent probe amplification (MLPA) was performed in all participants for the detection of larger copy number variations (CNVs). Sanger sequencing was undertaken for the detection of point variants, small deletions, and insertions. A total of one deletion and two duplications were discovered using the MLPA technique. Only one of these four variants was identified as disease-causing and occurred in one individual, which represents 1.3% of the cohort. With Sanger sequencing, two variants were discovered, but none of them appeared to have a pathogenic effect on height. According to the results, in the Slovenian population of children and young adults with ISS, SHOX deficiency is less frequent than expected considering existing data from other populations. Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)

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19 pages, 808 KiB

Open AccessEditor’s ChoiceReview

Pathogenesis of Type 1 Diabetes: Established Facts and New Insights

by Ana Zajec, Katarina Trebušak Podkrajšek, Tine Tesovnik, Robert Šket, Barbara Čugalj Kern, Barbara Jenko Bizjan, Darja Šmigoc Schweiger, Tadej Battelino and Jernej Kovač

Genes 2022, 13(4), 706; https://doi.org/10.3390/genes13040706 - 16 Apr 2022

Cited by 19 | Viewed by 15266

Abstract

Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing β-cells in pancreatic islets. It generally occurs in genetically susceptible individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous [...] Read more.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the T-cell-mediated destruction of insulin-producing β-cells in pancreatic islets. It generally occurs in genetically susceptible individuals, and genetics plays a major role in the development of islet autoimmunity. Furthermore, these processes are heterogeneous among individuals; hence, different endotypes have been proposed. In this review, we highlight the interplay between genetic predisposition and other non-genetic factors, such as viral infections, diet, and gut biome, which all potentially contribute to the aetiology of T1D. We also discuss a possible active role for β-cells in initiating the pathological processes. Another component in T1D predisposition is epigenetic influences, which represent a link between genetic susceptibility and environmental factors and may account for some of the disease heterogeneity. Accordingly, a shift towards personalized therapies may improve the treatment results and, therefore, result in better outcomes for individuals in the long-run. There is also a clear need for a better understanding of the preclinical phases of T1D and finding new predictive biomarkers for earlier diagnosis and therapy, with the final goal of reverting or even preventing the development of the disease. Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)

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12 pages, 782 KiB

Open AccessReview

The Role of Epigenetic Modifications in Late Complications in Type 1 Diabetes

by Barbara Čugalj Kern, Katarina Trebušak Podkrajšek, Jernej Kovač, Robert Šket, Barbara Jenko Bizjan, Tine Tesovnik, Maruša Debeljak, Tadej Battelino and Nataša Bratina

Genes 2022, 13(4), 705; https://doi.org/10.3390/genes13040705 - 15 Apr 2022

Cited by 10 | Viewed by 3129

Abstract

Type 1 diabetes is a chronic autoimmune disease in which the destruction of pancreatic β cells leads to hyperglycemia. The prevention of hyperglycemia is very important to avoid or at least postpone the development of micro- and macrovascular complications, also known as late [...] Read more.

Type 1 diabetes is a chronic autoimmune disease in which the destruction of pancreatic β cells leads to hyperglycemia. The prevention of hyperglycemia is very important to avoid or at least postpone the development of micro- and macrovascular complications, also known as late complications. These include diabetic retinopathy, chronic renal failure, diabetic neuropathy, and cardiovascular diseases. The impact of long-term hyperglycemia has been shown to persist long after the normalization of blood glucose levels, a phenomenon known as metabolic memory. It is believed that epigenetic mechanisms such as DNA methylation, histone modifications, and microRNAs, play an important role in metabolic memory. The aim of this review is to address the impact of long-term hyperglycemia on epigenetic marks in late complications of type 1 diabetes. Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)

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16 pages, 6680 KiB

Open AccessReview

Aberrant DNA Methylation Mediates the Transgenerational Risk of Metabolic and Chronic Disease Due to Maternal Obesity and Overnutrition

by Yan Li, Carol A. Pollock and Sonia Saad

Genes 2021, 12(11), 1653; https://doi.org/10.3390/genes12111653 - 20 Oct 2021

Cited by 8 | Viewed by 2899

Abstract

Maternal obesity is a rapidly evolving universal epidemic leading to acute and long-term medical and obstetric health issues, including increased maternal risks of gestational diabetes, hypertension and pre-eclampsia, and the future risks for offspring’s predisposition to metabolic diseases. Epigenetic modification, in particular DNA [...] Read more.

Maternal obesity is a rapidly evolving universal epidemic leading to acute and long-term medical and obstetric health issues, including increased maternal risks of gestational diabetes, hypertension and pre-eclampsia, and the future risks for offspring’s predisposition to metabolic diseases. Epigenetic modification, in particular DNA methylation, represents a mechanism whereby environmental effects impact on the phenotypic expression of human disease. Maternal obesity or overnutrition contributes to the alterations in DNA methylation during early life which, through fetal programming, can predispose the offspring to many metabolic and chronic diseases, such as non-alcoholic fatty liver disease, obesity, diabetes, and chronic kidney disease. This review aims to summarize findings from human and animal studies, which support the role of maternal obesity in fetal programing and the potential benefit of altering DNA methylation to limit maternal obesity related disease in the offspring. Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)

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7 pages, 449 KiB

Open AccessCase Report

An Adolescent Boy with Klinefelter Syndrome and 47,XXY/46,XX Mosaicism: Case Report and Review of Literature

by Tinka Hovnik, Eva Zitnik, Magdalena Avbelj Stefanija, Sara Bertok, Katarina Sedej, Vesna Bancic Silva, Tadej Battelino and Urh Groselj

Genes 2022, 13(5), 744; https://doi.org/10.3390/genes13050744 - 23 Apr 2022

Cited by 1 | Viewed by 5514

Abstract

Klinefelter syndrome is the most commonly reported sex chromosome abnormality. It is heavily underdiagnosed due to the substantial variability of clinical presentations but is generally characterized by small, firm testes, hypergonadotropic hypogonadism, and the absence of spermatogenesis. Most patients with Klinefelter syndrome have [...] Read more.

Klinefelter syndrome is the most commonly reported sex chromosome abnormality. It is heavily underdiagnosed due to the substantial variability of clinical presentations but is generally characterized by small, firm testes, hypergonadotropic hypogonadism, and the absence of spermatogenesis. Most patients with Klinefelter syndrome have a 47,XXY genotype. If they present with mosaicism, two different cell lines are usually identified, an aneuploid 47,XXY cell line and a normal male 46,XY cell line. There are very few cases of 47,XXY mosaicism with the additional female cell line 46,XX described in the literature. We report a case of an adolescent with the male phenotype and a rare variant mosaic 47,XXY/46,XX karyotype who presented with painless bilateral gynaecomastia. 47,XXY and 46,XX mosaic cell lines were identified with GTG-banding and further characterized using fluorescent in situ hybridization. We summarized the available clinical presentations of reported male patients with 47,XXY/46,XX mosaicism. To improve the clinical management and quality of life in individuals with rare and cryptic genomic imbalances, the genetic diagnosis would need to be extended to atypical cases. Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Endocrine Disorders)

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