HDL subgroups and their paraoxonase-1 activity in the obese, overweight and normal weight subjects.

BACKGROUND: Obesity and overweight are significant public health problems because of higher risk for coronary artery disease (CAD). It is very important to determine new predictive markers to identify the CAD risk in obese and overweight. To aim this, we analysed HDL-C subgroups (HDL2-C and HDL3-C) and their paraoxonase-1 (PON-1) activity in obese, overweight and normal weight subjects. METHOD: 71 obese, 40 overweight and 30 healthy subjects as a control group were enrolled the study. Serum lipids levels were determined with enzymatic colorimetric method. Further, PON-1 activities and HDL-C levels were determined by spectrophotometric methods. Non-HDL3-C concentrations were calculated with the subtraction of HDL3-C from total HDL-C. RESULTS: The mean serum levels of total HDL-C, HDL3-C, Non-HDL3-C and ApoA1 were higher in control group than obese and overweight groups. There were a statistically significant difference between obese and control group in terms of Lp(a), hsCRP and HOMA index. Higher total PON-1, non-HDL3 PON-1 and HDL3 PON-1 activities were found in the control group compared with obese and overweight groups. Total HDL was weakly negative correlated with the HOMA index, BMI and waist circumference. There was a weak negative correlation between non-HDL3-C and waist circumference. CONCLUSION: Altered HDL-subgroups pattern and decreased PON-1 activities may cause increased risk for CVD in obese and overweight individuals. Therefore determination of HDL subgroups and their PON-1 activity may improve risk prediction compared with measuring total HDL-C levels and its PON-1 activity alone. Body weight and insulin resistance appear to have a role in the decreased HDL-C levels and PON-1activity in obese. Further studies should be conducted to shed more light on impacts of these markers in CVD.

Severe brachydactyly and short stature resulting from a novel pathogenic TRPS1 variant within the GATA DNA-binding domain.

Brachydactyly type E, which can be an isolated finding or part of a syndrome in combination with other clinical anomalies, involves metacarpals and metatarsals with or without short phalanges. Herein we report two unrelated Turkish females who presented with brachydactyly type E and vitamin D deficiency in the absence of marked alterations in serum calcium, phosphate, and parathyroid hormone. After excluding disease-causing variants in two candidate genes, PTHLH and PDE4D, we identified different pathogenic variants in TRPS1, the gene mutated in patients with tricho-rhino-phalangeal syndrome (TRPS). In one of the patients, who displayed severe brachydactyly and short stature, we identified a novel heterozygous missense pathogenic variant in exon 6 (c.2783A>G, p.Tyr928Cys), located within the GATA DNA-binding domain. The second patient, who had relatively milder brachydactyly and was of normal height, carried a heterozygous nonsense pathogenic variant in exon 4 (c. 1870C>T, p.Arg624Ter), which has been previously described. Both pathogenic variants segregated in affected family members. The patients additionally showed sparse hair and a bulbous nose, consistent with the clinical features of TRPS. Our findings, in addition to identifying the genetic cause of brachydactyly in two unrelated kindreds, emphasize the role of pathogenic TRPS1 variants in the development of brachydactyly type E and highlight the GATA DNA-binding region of TRPS1 protein with respect to phenotype-genotype correlation.

Decreased Spexin Levels in Patients with Type 1 and Type 2 Diabetes.

BACKGROUND/AIMS: Spexin is a novel peptide which has a potential role as a biomarker of insulin resistance, diabetes, and obesity. Our aim was to measure spexin levels in lean type 1 diabetic patients and its relevance to glycemic parameters without the presence of obesity or insulin resistance. SUBJECTS AND METHODS: This cross-sectional study included 29 type 1 and 30 type 2 diabetic patients and a control group of 23 healthy subjects with adjusted age, sex, and body mass index (BMI). Height and weight were measured using standard techniques. Glucose levels, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, serum cortisol levels, and spexin levels were measured in each patient. RESULTS: The median fasting serum spexin levels were significantly lower in patients with type 1 and type 2 diabetes than in control subjects (p = 0.008 and p = 0.041, respectively). Spexin levels were not correlated with glycemic parameters, lipids, BMI, cortisol levels, and thyroid-stimulating hormone (p > 0.05). Only age turned out to be correlated with spexin levels in patients with type 1 diabetes when we analyzed the groups separately. Regression models, including age and diabetes duration, revealed no association between age and spexin levels. Regression models, including cortisol, BMI, and HbA1c, revealed no association with spexin levels within each group. CONCLUSION: The presence of type 1 diabetes is associated with lower spexin levels, independent of glucose, lipid parameters, and BMI. The expression of spexin in the pancreas apart from the current glycemic control of the patients may be the main determinant of spexin levels in type 1 diabetic patients.

Homozygous Mutation in Human Serum Albumin and Its Implication on Thyroid Tests.

An individual with familial dysalbuminemic hyperthyroxinemia (FDH) due to a homozygous mutation (c.653G>A, p.R218H) in the human serum albumin (HSA) gene is reported. The patient was identified during evaluation of abnormal thyroid tests in a large family with multiple levels of consanguinity. He showed a greater increase in total thyroxine (T4) relative to that observed in heterozygous family members. The higher affinity of mutant HSA for T4, together with the large molar excess of HSA relative to thyroid hormones in serum, results in preferential association of T4 with the mutant rather than wild-type HSA in heterozygous individuals. The twofold greater amount of T4 bound to the mutant HSA in the homozygote, relative to heterozygotes, is an adaptive requirement to maintain a normal free T4 concentration.

Constitutive stimulatory G protein activity in limb mesenchyme impairs bone growth.

GNAS mutations leading to constitutively active stimulatory G protein alpha-subunit (Gsα) cause different tumors, fibrous dysplasia of bone, and McCune-Albright syndrome, which are typically not associated with short stature. Enhanced signaling of the parathyroid hormone/parathyroid hormone-related peptide receptor, which couples to multiple G proteins including Gsα, leads to short bones with delayed endochondral ossification. It has remained unknown whether constitutive Gsα activity also impairs bone growth. Here we generated mice expressing a constitutively active Gsα mutant (Gsα-R201H) conditionally upon Cre recombinase (cGsαR201H mice). Gsα-R201H was expressed in cultured bone marrow stromal cells from cGsαR201H mice upon adenoviral-Cre transduction. When crossed with mice in which Cre is expressed in a tamoxifen-regulatable fashion (CAGGCre-ER™), tamoxifen injection resulted in mosaic expression of the transgene in double mutant offspring. We then crossed the cGsαR201H mice with Prx1-Cre mice, in which Cre is expressed in early limb-bud mesenchyme. The double mutant offspring displayed short limbs at birth, with narrow hypertrophic chondrocyte zones in growth plates and delayed formation of secondary ossification center. Consistent with enhanced Gsα signaling, bone marrow stromal cells from these mice demonstrated increased levels of c-fos mRNA. Our findings indicate that constitutive Gsα activity during limb development disrupts endochondral ossification and bone growth. Given that Gsα haploinsufficiency also leads to short bones, as in patients with Albright's hereditary osteodystrophy, these results suggest that a tight control of Gsα activity is essential for normal growth plate physiology.

A novel deletion involving GNAS exon 1 causes PHP1A and further refines the region required for normal methylation at exon A/B.

GNAS exons 1-13 encode the biallelically expressed alpha-subunit of the stimulatory G protein (Gαs). Additional transcripts derived from this locus use alternative first exons that undergo parent-specific methylation, thus allowing transcription only from the non-modified allele. Pseudohypoparathyroidism type Ia (PHP1A) is characterized by Albright's Hereditary Osteodystrophy (AHO) and resistance to multiple hormones; this disorder is caused by maternal inactivating mutations involving Gαs exons. In contrast, pseudohypoparathyroidism type Ib (PHP1B) is characterized mostly by resistance to PTH and often mild TSH resistance, usually without AHO features. The autosomal dominant variant of PHP1B (AD-PHP1B) is caused by maternal deletions in GNAS or STX16 that reduce Gαs expression through loss-of-methylation at GNAS exon A/B alone or at multiple differentially methylated regions (DMR). Several large maternal deletions involve not only GNAS exons 1-13, but also one or several GNAS DMRs, thus causing PHP1A combined with apparent GNAS epigenetic changes that are indistinguishable from those observed in PHP1B. Some of these deletions include a large CpG island extending from exon A/B to the intron between GNAS exons 1 and 2, but there is no evidence for parent-specific exon 1 methylation. We now describe a family in which the female proband and her daughter presented with hypocalcemia, elevated PTH levels, shortened metacarpals, and obesity, but without obvious neurocognitive abnormalities. A maternally inherited 2015-bp deletion that includes GNAS exon 1 was identified thereby establishing the diagnosis of PHP1A. The centromeric deletion breakpoint is located 178bp upstream of exon 1, yet no methylation changes were observed at exon A/B. This novel deletion therefore refines further the region between exon A/B and exon 1 that is critical for establishing or maintaining normal methylation at GNAS exon A/B.

Neopterin and hsCRP are not correlated in gestational diabetes mellitus.

OBJECTIVE: To determine serum neopterin and high sensitive C-reactive protein (hsCRP) levels in patients with and without gestational diabetes mellitus (GDM). METHODS: Neopterin and hsCRP levels were quantified in 28 women with GDM and 20 pregnant women with normal glucose tolerance (NGT). Postpartum neopterin and hsCRP levels were measured in a follow-up study. RESULTS: Neopterin levels were significantly higher in women with GDM than in women with NGT (15.89 ± 8.19 nmol/L versus 10.4 ± 3.8 nmol/L, p < 0.008, respectively), however the levels significantly decreased after delivery in GDM group (15.89 ± 8.19 nmol/L versus 11.63 ± 5.96 nmol/L, p < 0.001). hsCRP levels were not different between women with and without GDM (5.74 ± 3.91 versus 5.73 ± 3.34, p = 0.9, respectively). In contrast, hsCRP levels decreased after delivery in patients with GDM (5.74 ± 3.91 versus 3.78 ± 2.78, p < 0.01). Neopterin levels were correlated with maternal age (r = 0.3, p = 0.02) and fasting glucose (r = 0.4, p = 0.004), postprandial glucose (r = 0.3, p = 0.01), HbA1c (r = 0.3, p = 0.02), whereas hsCRP levels were correlated with pre-pregnancy (r = 0.3, p = 0.04) and pregnancy body mass index (r = 0.4, p = 0.008). No correlation between serum neopterin and hsCRP levels was found (p = 0.9). CONCLUSION: Neopterin levels increased in patients with GDM; hence, it may be related to inflammation. However, the lack of correlation between neopterin and hsCRP suggests the role of different attitudes of these two parameters in the course of pregnancy and GDM.