Clinical implications of the glucokinase impaired function - GCK MODY today.

Heterozygous inactivating mutations of the glucokinase (GCK) gene are causing GCK-MODY, one of the most common forms of the Maturity Onset Diabetes of the Young (MODY). GCK-MODY is characterized by fasting hyperglycemia without apparent worsening with aging and low risk for chronic vascular complications. Despite the mild clinical course, GCK-MODY could be misdiagnosed as type 1 or type 2 diabetes. In the diagnostic process, the clinical suspicion is often based on the clinical diagnostic criteria for GCK-MODY and should be confirmed by DNA analysis. However, there are several issues in the clinical and also in genetic part that could complicate the diagnostic process. Most of the people with GCK-MODY do not require any pharmacotherapy. The exception are pregnant women with a fetus which did not inherit GCK mutation from the mother. Such a child has accelerated growth, and has increased risk for diabetic foetopathy. In this situation the mother should be treated with substitutional doses of insulin. Therefore, distinguishing GCK-MODY from gestational diabetes in pregnancy is very important. For this purpose, special clinical diagnostic criteria for clinical identification of GCK-MODY in pregnancy are used. This review updates information on GCK-MODY and discusses several currently not solved problems in the clinical diagnostic process, genetics, and treatment of this type of monogenic diabetes.

Immunologic phenotype of a child with the MEHMO syndrome.

MEHMO syndrome is a rare X-linked syndrome characterized by Mental retardation, Epilepsy, Hypogenitalism, Microcephaly, and Obesity associated with the defect of protein synthesis caused by the EIF2S3 gene mutations. We hypothesized that the defect in protein synthesis could have an impact on the immune system. We describe immunologic phenotype and possible treatment outcomes in patient with MEHMO syndrome carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. The proband (currently 9-year-old boy) had normal IgG and IgM levels, but had frequent respiratory and urinary tract infections. On subcutaneous immunoglobulin therapy achieving supra-physiological IgG levels the frequency of infections significantly decreased in Poisson regression by 54.5 % (CI 33.2-89.7, p=0.017). The MEHMO patient had had frequent acute infections despite normal IgG and IgM serum levels and responded well to the immunoglobulin treatment.

Hereditary bilateral sudden sensorineural hearing loss.

OBJECTIVES: The aim of our study is to demonstrate a causal link between two distinct diagnoses, the hereditary hearing loss, and the sudden sensorineural hearing loss. BACKGROUND: Sudden sensorineural hearing loss is an emergency condition in otolaryngology and a rare diagnosis in childhood. Most often it only affects one ear and its cause remains unknown. METHODS: We present a clinical study of a 10-year-old female patient presenting with bilateral sudden sensorineural hearing loss analyzed by Sanger sequencing of the GJB2 gene. RESULTS: The subject was referred to the hospital for bilateral sudden hearing loss which developed 3 days before the admission. Audiometric testing confirmed bilateral asymmetric sensorineural hearing loss. All routine diagnostic procedures including MRI and CT imaging showed normal results. She was treated with intravenous and intratympanic corticosteroids followed by hyperbaric oxygen therapy with partial hearing recovery in one ear. DNA analysis of the GJB2 gene identified biallelic c.35delG deletion. The subject had no other affected family members and her auditory development to that time was normal. CONCLUSION: Our finding extends the knowledge on phenotype variability in GJB2 variants. We suggest considering genetic testing in pediatric cases of bilateral sudden sensorineural hearing loss (Tab. 1, Fig. 4, Ref. 24).

Neonatal hypoglycemia, early-onset diabetes and hypopituitarism due to the mutation in EIF2S3 gene causing MEHMO syndrome.

Recently, the genetic cause of several syndromic forms of glycemia dysregulation has been described. One of them, MEHMO syndrome, is a rare X-linked syndrome recently linked to the EIF2S3 gene mutations. MEHMO is characterized by Mental retardation, Epilepsy, Hypogonadism/hypogenitalism, Microcephaly, and Obesity. Moreover, patients with MEHMO had also diabetes and endocrine phenotype, but detailed information is missing. We aimed to provide more details on the endocrine phenotype in two previously reported male probands with MEHMO carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. Both probands had a neonatal hypoglycemia, early onset insulin-dependent diabetes, and hypopituitarism due to dysregulation and gradual decline of peptide hormone secretion. Based on the clinical course in our two probands and also in previously published patients, neonatal hypoglycemia followed by early-onset diabetes and hypopituitarism may be a consistent part of the MEHMO phenotype.

Sulfonylurea vs insulin therapy in individuals with sulfonylurea-sensitive permanent neonatal diabetes mellitus, attributable to a KCNJ11 mutation, and poor glycaemic control.

BACKGROUND: Therapy with sulfonylurea is preferable to insulin in the majority of individuals with KCNJ11 mutations, but not all of these people achieve target levels of HbA1c in long-term follow-up. We aimed to compare sulfonylurea therapy with insulin treatment in two sulfonylurea-sensitive individuals with a KCNJ11 mutation who had poorly controlled permanent neonatal diabetes mellitus. CASE REPORT: We report on two individuals with a KCNJ11 mutation (p.R201H) who are currently aged 35 (SVK1) and 21 years (SVK2). These individuals were switched from insulin to sulfonylurea in 2005. Data from the first 4 (SVK2) and 8 years (SVK1) of the follow-up showed improved diabetes control and increased quality of life for both individuals. During the following years, however, both individuals failed to retain good diabetes control (HbA1c ≤ 53 mmol/mol; 7.0%). We therefore changed the therapy to a combination of insulin and sulfonylurea in both individuals, or to insulin monotherapy in SVK1, and compared the effects on HbA1c with those of sulfonylurea monotherapy. HbA1c levels in both individuals worsened after adding insulin to sulfonylurea [67 mmol/mol (8.3%) vs 77 mmol/mol (9.2%) in SVK1 and 106 mmol/mol (11.8%) vs 110±19 mmol/mol (12.2±1.7%) in SVK2], and after switching to only insulin therapy in SVK1 [57 mmol/mol (7.4%) vs 62 mmol/mol (7.8%)] when compared with sulfonylurea monotherapy. DISCUSSION: Our data show that sulfonylurea monotherapy might be preferable to insulin in people with permanent neonatal diabetes mellitus sensitive to sulfonylurea even when HbA1c is above target.

The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey.

Familial hypercholesterolemia (FH) is most frequently caused by LDLR or APOB mutations. Therefore, the aim of our study was to examine the genetic background of Slovak patients suspected of FH. Patients with clinical suspicion of FH (235 unrelated probands and 124 family relatives) were recruited throughout Slovakia during the years 2011-2015. The order of DNA analyses in probands was as follows: 1. APOB mutation p.Arg3527Gln by real-time PCR method, 2. direct sequencing of the LDLR gene 3. MLPA analysis of the LDLR gene. We have identified 14 probands and 2 relatives with an APOB mutation p.Arg3527Gln, and 89 probands and 75 relatives with 54 different LDLR mutations. Nine of LDLR mutations were novel (i.e. p.Asp90Glu, c.314-2A>G, p.Asp136Tyr, p.Ser177Pro, p.Lys225_Glu228delinsCysLys, p.Gly478Glu, p.Gly675Trpfs*42, p.Leu680Pro, p.Thr832Argfs*3). This is the first study on molecular genetics of FH in Slovakia encompassing the analysis of whole LDLR gene. Genetic etiology of FH was confirmed in 103 probands (43.8 %). Out of them, 86.4 % of probands carried the LDLR gene mutation and remaining 13.6 % probands carried the p.Arg3527Gln APOB mutation.

Age of obesity onset in MC4R mutation carriers.

OBJECTIVES: The mutations in gene for the melanocortin-4 receptor (MC4R) are the most common etiology factors of monogenic obesity development. Recently, it has been shown that current life style has a significant impact on the phenotype of MC4R mutation carriers - increases the penetrance of the mutations. We aimed to study the impact of the current age on the time of obesity onset among MC4R mutation carriers. METHODS: DNA analysis of the MC4R gene was performed in 268 unrelated Slovak and Moravian obese children and adolescents 18 years and 28 blood relatives >18 years of the probands with a mutation. RESULTS: Three different previously described heterozygous loss of function MC4R mutations (p.Ser19Alafs*34, p.Ser127Leu, and p.Gly181Asp) were found in 3 <18 years probands, 3 adult probands, and 6 adult obese/overweight family relatives. The age of obesity onset in mutation carriers was 1 year in all probands in the children group and 1-35 years (median 11 years) in adults. The age of the obesity onset significantly correlated (R=0.809, p=0.028) with the current age in all of the MC4R mutation carriers. CONCLUSIONS: The age of obesity onset in the present child generation of MC4R mutation carriers is decreasing compared to the age of onset in their parents' generation. This is in agreement with similarly increasing penetrance of obesity in MC4R mutation carriers and it points out to escalation of obesogenic potential of environment.

Molecular-genetic aspects of familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is the world's most abundant and the most common heritable disorder of lipid metabolism. The prevalence of the disease in general population is 1:500. Therefore the approximate number of FH patients all over the world is 14 million. From the genetic point of view the disease originates as a result of mutations in genes affecting the processing of LDL particles from circulation, resulting in an increase in LDL cholesterol and hence total cholesterol. These are mutations in genes encoding LDL receptor, apolipoprotein B, proprotein convertase subtilisin/kexin 9 and LDL receptor adaptor protein 1. Cholesterol depositing in tissues and blood vessels of individuals creates tendon xanthoma, xanthelesma and arcus lipoides cornae. Due to the increased deposition of cholesterol in blood vessels, atherosclerosis process is accelerated, what leads to a significantly higher risk of premature cardiovascular diseases. Therefore, early clinical diagnosis confirmed by the DNA analysis, and effective treatment are crucial to reduce the mortality and high risk of premature atherosclerotic complications.

Melanocortin-4 receptor gene mutations in obese Slovak children.

The most common etiology of non-syndromic monogenic obesity are mutations in gene for the Melanocortin-4 receptor (MC485) with variable prevalence in different countries (1.2-6.3 % of obese children). The aim of our study was 1) to search for MC4R mutations in obese children in Slovakia and compare their prevalence with other European countries, and 2) to describe the phenotype of the mutation carriers. DNA analysis by direct Sanger sequencing of the coding exons and intron/exon boundaries of the MC4R gene was performed in 268 unrelated Slovak children and adolescents with body mass index above the 97(th) percentile for age and sex and obesity onset up to 11 years (mean 4.3+/-2.8 years). Two different previously described heterozygous loss of function MC4R variants (i.e. p.Ser19Alafs*34, p.Ser127Leu) were identified in two obese probands, and one obese (p.Ser19Alafs*34), and one lean (p.Ser127Leu) adult family relatives. No loss of function variants were found in lean controls. The prevalence of loss-of-function MC4R variants in obese Slovak children was 0.7 %, what is one of the lowest frequencies in Europe.

Obesogenic and diabetogenic impact of high organochlorine levels (HCB, p,p'-DDE, PCBs) on inhabitants in the highly polluted Eastern Slovakia.

OBJECTIVE: This study was aimed to evaluate possible obesogenic and diabetogenic impact of highly increased serum level of persistent organochlorinated pollutants POPs, such as polychlorinated biphenyls (PCBs), dichlorodiethyl-dichloroethylene (p,p'-DDE), and hexachlorobenzene (HCB), on the level of obesity markers (cholesterol and triglyceride level in serum, and body mass index [BMI]) and diabetes markers (fasting glucose and fasting insulin in serum) in inhabitants of Eastern Slovakia. METHODS: In young (21-40 years) males (n=248) and females (n=330) as well as in old (41-75 years) males (n=586) and females (n=889), the serum levels of 15 polychlorinated biphenyl congeners (Σ15PCBs), p,p'-DDE and HCB, and serum insulin, testosterone, total cholesterol, triglycerides and glucose levels have been estimated by high resolution gas chromatography/mass spectrometry and by the appropriate electrochemiluminiscent immunoassay or chemical methods, respectively. RESULTS: In both age groups of males and females, the levels of Σ15PCBs, p,p'-DDE, and HCB were very high and their mutual interrelations were highly significant (p<0.01). However, it should be noted that no significant changes were found in individual variables related to very high level of Σ15PCBs, except of increased BMI (p>0.05) in females.In all ages and gender groups, defined above general as related to increasing level of individual OCPs in individual age and gender groups, significant increase in cholesterol and triglyceride levels as well as BMI values, supported their obesogenic effect, while significant increase in fasting glucose and insulin in serum, supported their diabetogenic effect. Finally, highly significant decrease in testosterone level, as found in both young and old males, supported the antiandrogenic effect, namely of HCB. However, somewhat less of p,p'-DDE, while PCBs did not show any such effect in spite of their very high level. CONCLUSIONS: Highly increased blood levels of diabetes (fasting glucose and insulin) and obesity markers (cholesterol, triglyceride and BMI) were found in large groups of males and females in highly polluted area of Slovakia. Significant decrease in testosterone level was also observed in males.

Prevalence of DFNB1 mutations among cochlear implant users in Slovakia and its clinical implications.

Hereditary etiology plays an important role in bilateral profound deafness as a main indication for cochlear implantation. Mutations in DFNB1 locus account for most of the inherited deafness cases in Caucasians. To provide actual data on mutation prevalence among implanted deaf subpopulation, we performed DNA analysis of GJB2 and GJB6 genes in 131 unrelated Slovak cochlear implant users. Eight previously described causal mutations and one probably pathogenic missense variant (c.127G>A) were detected in the GJB2 gene in 58 (44.28%) subjects. The most common mutation found was c.35delG with frequency 83.02% of all disease alleles, followed by c.71G>A, c.1-3201G>A, c.313_326del14, c.109G>A, 167delT, c.269T>C, and c.333_334delAA. GJB6 deletion delD13S1830 was identified in only one subject, in double heterozygosity with a GJB6 mutation. Thus, the deafness cause could be clearly attributable to DFNB1 mutations in 36.64% of the patients examined. In summary, the mutation profile found in our cohort was similar to the mutation spectrum reported for Central European deaf populations. The mutation prevalence in cochlear implant users was, however, almost by 25% higher than previously established for non-implanted hearing-impaired population in Slovakia. Finally, we also demonstrate a certain variability in deafness onset in patients with causal genotype and coincidence with other risk factors for deafness. Our results underline the importance of genetic tests in all cochlear implant candidates.

Effects of hypoxia on adipose tissue expression of NFκB, IκBα, IKKγ and IKAP in patients with chronic obstructive pulmonary disease.

Recently we observed increased adipose tissue (AT) expression of CD40-related signaling proteins but no activation of tumor necrosis factor-α or CD68 in patients with chronic sustained hypoxia resulting from chronic obstructive pulmonary disease (COPD). Transcription factor nuclear factor-κB (NFκB) is involved in cellular responses to hypoxia and activates the proinflammatory gene expression with concomitant upregulation of its own repressors--inhibitors of κB (IκB) in an auto feedback loop. Inhibitor of kappaB kinase (IKK)-γ and inhibitor of kappaB kinase complex-associated protein (IKAP) are further regulatory proteins involved in NFκB signaling. In this study, we hypothesized that chronic sustained hypoxia significantly relates to IκBα, IKKγ and IKAP within the AT in COPD patients. In 20 patients with stable disease, samples of subcutaneous AT were analyzed using real-time PCR. Although no significant differences were observed between two groups categorized by median PaO2 in NFκB (p = 0.065), gene expressions of IκBα, IKKγ and IKAP were all higher in hypoxemic patients (p = 0.033; p = 0.050; p = 0.010, respectively). In multivariate analyses, PaO2 independently predicted AT IκBα, IKKγ and IKAP (R (2) = 0.490, p = 0.012; R (2) = 0.586, p = 0.002; R (2) = 0.504, p = 0.009, respectively). In conclusion, our data suggest significant AT upregulation of IκBα, IKKγ and IKAP by chronic sustained hypoxia in COPD patients.

Circulatory and adipose tissue leptin and adiponectin in relationship to resting energy expenditure in patients with chronic obstructive pulmonary disease.

Increases in resting energy expenditure (REE) likely contribute to weight loss in various chronic diseases. In chronic obstructive pulmonary disease (COPD), relationships between the ventilatory impairment and increased REE, and between disturbances in adipokines and weight loss were previously described. Therefore, we investigated serum levels and adipose tissue expression of leptin and adiponectin, and their relationships to REE in patients with COPD. In 44 patients with stable COPD (38 male; age 62.3+/-7.2 years), REE was assessed using indirect calorimetry. Subcutaneous adipose tissue samples were analyzed using real-time PCR. From underweight [n=9; body mass index (BMI) <20.0 kg.m(-2)], to normal weight-overweight (n=24, BMI=20.0-29.9 kg.m(-2)) and obese patients (n=11; BMI>/=30 kg.m(-2)), REE adjusted for body weight decreased (32.9+/-6.1 vs. 26.2+/-5.8 vs. 23.9+/-6.6 kcal.kg(-1).24 h(-1), p=0.006), serum levels and adipose tissue expression of leptin increased (p<0.001 for both), and serum and adipose tissue adiponectin decreased (p<0.001; p=0.004, respectively). REE was inversely related to serum and adipose tissue leptin (R=-0.547, p<0.001; R=-0.458, p=0.002), and directly to serum adiponectin (R=0.316, p=0.039). Underweight patients had increased REE compared to normal weight-overweight patients, in association with reductions in serum and adipose tissue leptin, and increased serum adiponectin, suggesting a role of adipokines in energy imbalance in COPD-related cachexia.

Molecular and hereditary mechanisms of sensorineural hearing loss with focus on selected endocrinopathies.

Hearing loss is one of the most widespread sensory disorders. The incidence of deafness in general population is 1:1000 newborns. About one half of the cases of the congenital sensorineural hearing loss (SNHL) is inherited. Recessive mutations in the gap junction beta 2 (GJB2) gene are the most common genetic causes of the nonsyndromic SNHL. The GJB2 encodes a protein connexin 26 which forms a subunit of gap junction essential for the correct function of the inner ear. The syndromic SNHL is associated with a wide range of other symptoms, which encompass also dysfunctions of endocrine organs. The Pendred syndrome associated with the hearing impairment is characterized by a prelingual, bilateral sever to profound SNHL, goiter, and iodine organification defect. It is an autosomal recessive disorder, which develops due to mutations in pendrin, an anion channel encoded by SLC26A4 gene. Another important type of syndromic hearing loss is the Maternally Inherited Diabetes and Deafness syndrome, which is caused by several mitochondrial DNA mutations. These mutations are clinically manifested by a hearing impairment with development of the diabetes in the adult age. Hearing impairment occurs during puberty when sensation of high frequency tones is affected following with further progress to profound bilateral sensorineural hearing impairment in the whole frequency range. This review deals with the molecular mechanisms of common genetic causes of the hereditary SNHL along with the selected endocrinopathies emphasizing that the DNA analyses along with the functional studies significantly contribute to the early SNHL diagnosis followed by personalized therapy and genetic counseling.

Impact of Type 2 diabetes on Glucokinase diabetes (GCK-MODY) phenotype in a Roma (Gypsy) family - case report.

OBJECTIVES: Glucokinase (GCK) diabetes is a mild form of the monogenic diabetes characterized by the fasting hyperglycemia without signs of metabolic syndrome and very low risk for chronic complications of diabetes. For the Type 2 diabetes (T2D), signs of the metabolic syndrome with high risk for chronic micro- and macro-vascular complications are typical. The prevalence of the GCK-diabetes is estimated from 0.5 to 1% in the diabetic patients. The T2D is the most prevalent type of the diabetes (it encompasses more than 85% of all the diabetic patients). According to the epidemiology, the coincidence of these two diabetes subtypes may occur; nevertheless no case reports on the above mentioned two diabetes subtypes have been published. The aim of the study was: 1) to perform the DNA analysis in three brothers, two of them with the fasting hyperglycemia and one with normal glucose tolerance, and their father with T2D metabolic syndrome and 2) to study the coincidence of the GCK-diabetes with T2D and its effect on the diabetic phenotype. PATIENTS AND METHODS: We report about a Roma (Gypsy) family consisting of three brothers: 17 years old probant and two older brothers (21 and 25 years), and their father. The probant is suffering from fasting hyperglycemia. His 25 years old diabetic brother and their father suffer from obesity, hypertension, dyslipidemia, and hyperglycemia. The glucokinase gene was analyzed by direct sequencing in each of the brothers and their father, and appropriate phenotype characteristics were also carried out on each of the family members. RESULTS: In the proband and his diabetic brother with the fasting hyperglycemia, a heterozygous mutation of the glucokinase gene p.Arg36Trp was found. The proband's phenotype was consistent with the GCK-diabetes, while the diabetic brother displayed already features of the metabolic syndrome. Although, the latter one suffered from the overweight, hypertension, and elevated triglycerides, his fasting hyperglycemia (8.3 mmol/l) was still consistent with the GCK-diabetes. Their father is also a heterozygous mutation carrier of the same mutation displaying all the features of the metabolic syndrome. In his case, the fasting hyperinsulinemia (43.5 µU/ml) and fasting plasma glucose (10.4 mmol/l) are more typical for the T2D than GCK-diabetes. CONCLUSIONS: We found coincidence between the GCK-diabetes and T2D in the members of a single Roma (Gypsy) family. Since the chronic complications are rare in the GCK-diabetes, the major risk factor for the further morbidity may be in the development of the T2D. The overlapping of the GCK-diabetes with other types of diabetes, particularly the T2D, makes the diagnostics difficult and therefore, it might be one of the reasons why the estimated prevalence of the GCK-diabetes seems to be higher than the real one as it has been reported in several studies.

[Genetics of monogenic forms of diabetes]. / Genetika monogénových foriem diabetu.

Monogenic diabetes mellitus is a type of diabetes, where genetics without any other factors is strong enough to cause the disease. According to the clinical features monogenic diabetes can be divided to the mild familial early onset diabetes, familial fasting hyperglycemia, diabetes with extrapancreatic features and neonatal diabetes mellitus. During the last several years the number of genes causing monogenic diabetes has continuously increased. The clinical picture of the monogenic diabetes is very heterogeneous, thus DNA analysis is required for identification of the diabetes etiology, which influences also the choice of treatment. This article is an overview of current knowledge on monogenic diabetes, focusing at the clinically and epidemiologically most important forms.

A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes.

AIMS/HYPOTHESIS: An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed. Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that high-sensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays. METHODS: High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n = 457), glucokinase (GCK)-MODY (n = 404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (n = 54) and type 2 diabetes (n = 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values >10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curve-derived C-statistic. RESULTS: In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (z score -21.8, p < 5 × 10(-105)). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l, p < 5 × 10(-5)). High-sensitivity CRP values between assays were strongly correlated (r (2) ≥ 0.91, p ≤ 1 × 10(-5)). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy. CONCLUSIONS/INTERPRETATION: In the largest study to date, we have established that hsCRP is a clinically valid biomarker for HNF1A-MODY in European populations. Given the modest costs and wide availability, hsCRP could translate rapidly into clinical practice, considerably improving diagnosis rates in monogenic diabetes.

[Clinical and genetic aspects of monogenic obesity]. / Klinické a genetické aspekty monogénovej obezity.

High prevalence of obesity in all of age categories is currently one of the biggest problem in medicine. Identification of etiology of obesity can individualise an approach to the patient and it is essential for choosing a target management and therapy. Beside the largest group with polygenic inheritance are clinically important also patients with "syndromic obesity", where obesity is only one of the signs and monogenic obesity, where obesity is the major clinical phenotype (patients with mutations in gene for leptin, leptine receptor, prohormone convertase 1, melanocortine receptor 4, brain-derived neurotropic factor and tyrosin kinase receptor B). The monogenic obesity includes 3-4% of all patients with obesity. This review article brings newest insight on genetics, clinical manifestation, diagnostics and therapy of these diseases.

Novel monogenic diabetes mutations in the P2 promoter of the HNF4A gene are associated with impaired function in vitro.

AIMS: Mutations in HNF4A cause a form of monogenic beta-cell diabetes. We aimed to identify mutations in the pancreas-specific P2 promoter of HNF4A in families with suspected HNF4A diabetes and to show that they impaired the function of the promoter in vitro. METHODS: We screened families with a clinical suspicion of HNF4A monogenic beta-cell diabetes for mutations in the HNF4A P2 promoter. We investigated the function of the previously reported HNF4A P2 promoter mutation -192C>G linked to late-onset diabetes in several families, along with two new segregating mutations, in vitro using a modified luciferase reporter assay system with enhanced sensitivity. RESULTS: We identified two novel HNF4A P2 promoter mutations that co-segregate with diabetes in two families, -136A>G and -169C>T. Both families displayed phenotypes typical of HNF4A monogenic beta-cell diabetes, including at least two affected generations, good response to sulphonylurea treatment and increased birthweight and/or neonatal hypoglycaemia. We show that both of these novel mutations and -192C>G impair the function of the promoter in transient transfection assays. CONCLUSIONS: Two novel mutations identified here and the previously identified late-onset diabetes mutation, -192C>G, impair the function of the HNF4A P2 promoter in vitro.