Nilüfer Bozkurt

The exon 3-deleted/full-length growth hormone receptor polymorphism and response to growth hormone therapy in growth hormone deficiency and Turner syndrome: a multicenter study.

Background/Aim: The exon 3-deleted/full-length (d3/fl) growth hormone (GH) receptor (GHR) polymorphism has been associated with responsiveness to GH therapy in some diagnostic groups. However, there are still controversies on this issue. To evaluate the effect of the GHR exon 3 polymorphism on growth after 1 and 2 years of GH therapy in Turkish patients with GH deficiency (GHD) and Turner’s syndrome (TS) and the distribution of GHR exon 3 isoforms. Materials and Methods: 218 patients with GHD (125 males/93 females) and 43 patients with TS were included in the study. The control group included 477 healthy adults aged from 18 to 57 years (54 females/423 males). Anthropometric parameters and insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 were evaluated annually. GHR isoforms were studied using simple multiplex PCR. Height and body mass index were expressed as standard deviation score (SDS). Results: There were no differences among TS, GHD and healthy adults regarding the distribution of GHR exon 3 isoforms (fl/fl, fl/d3 and d3/d3). There was a significant increase in height SDS in both diagnostic groups on GH therapy; however, there were neither differences in height SDS and Δheight velocity between fl/fl, fl/d3 and d3/d3 groups nor a correlation between the distribution of GHR exon 3 isoforms and change in IGF-1 SDS and IGFBP-3 SDS levels on GH therapy in either of the diagnostic groups. There was also no gender difference in GHR isoforms in healthy adults. Conclusion: The results suggest that responsiveness to GH therapy does not depend on the exon 3 GHR genotypes in GHD and TS patients.

Paraoxonase 1 192 and 55 polymorphisms in nephrotic children

Human paraoxonase 1 (PON1) is a serum enzyme related to high-density lipoprotein which has a major role in preventing oxidative modification of low-density lipoprotein. Due to its amino acid substitution PON1 has two genetic polymorphisms. These polymorphisms are characterized by the location of glutamine (A genotype) and arginine (B genotype) at position 192, and leucine (L genotype) and methionine (M genotype) at position 55. Hyperlipidemia and increased lipid oxidation in nephrotic syndrome may lead to glomerulosclerosis and progression of the glomerular disease. In this study we aimed to investigate PON1 192 and PON1 55 polymorphisms in children with focal segmental glomerulosclerosis (FSGS) and control subjects. The study included 25 children with biopsy-proven FSGS and 30 healthy controls. We demonstrated a statistically significant difference between FSGS patients and control subjects with respect to the distribution of the PON1 polymorphism. The AA genotype was less frequent and the AB+BB genotype was more frequent in FSGS patients than in controls (48 versus 73% for AA genotype and 52 versus 27% for AB+BB genotype, p<0.05). Distributions of PON1 55 genotypes of FSGS and control subjects were also statistically different (76 versus 43% for LL genotype and 24 versus 57% for LM+MM genotype, p<0.05) (case-control study, dominant model, Fisher’s exact test). The distributions of both genotypes in subgroups of FSGS (stable renal function versus declining renal function) were not statistically different. We conclude in this preliminary study that presence of B allele and/or L allele may be risk factors for the development of FSGS in children.

New MCAD gene mutation, not previously reported in other nations, found at A1161G in Turkish population

Medium chain acyl-CoA dehydrogenase (MCAD) catalyzes the ®rst reaction of the beta-oxidation cycle for 4-10-carbon fatty acids. MCAD de®ciency is one of the most frequent inborn metabolic disorders in populations of northwestern European origin [Tanaka et al., 1992]. It is also the most common defect in mitochondrial beta-oxidation in humans. It is an autosomal recessive disorder, which usually presents in infancy. The disease manifests itself in periods of metabolic stress to the beta-oxidation system and may be fatal. In previous reports, using a polymerase chain reaction (PCR)-based assay for 985A-to-G mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene, the following is demonstrated: ®rst, the A985G mutation in exon 11of MCAD gene is present more than 85% of the disease alleles from patients from all over the world; second, the allele frequency of A985G in the general population from most European countries is very high (1/59 in Netherlands, 1/68 in the United Kingdom, 1/74 in Scotland, 1/84 in Caucasian Americans in North Carolina, 1/101 in Denmark, 1/140 in France, and 1/143 in Normandy) [Andresen et al., 1995], but low in the southern part of western and central Europe (1/216 in Turkey, 1/240 in the Czech Republic, and 1/333 in Italy) [Tanaka et al., 1997]; third, these results support the notion of a founder effect in northwestern Europe [Yokota et al., 1991; Gregersen et al., 1993]; and fourth, MCAD de®ciency does not play a signi®cant role in the causation of SIDS [Miller et al., 1992; Arens et al., 1993; Ryan et al., 1997]. The prevalence of the 985A-to-G mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene among the Turkish population was studied using the PCR/Nco-I method for molecular diagnosis. A frequency study of this common mutation was also conducted on blood samples from 35 healthy newborns and their mothers. Neither heterozygotes nor homozygotes for the 985A-to-G mutation were identi®ed among newborns and their mothers. After considering previous reports, we stopped using the PCR/Nco-I method for molecular diagnosis, and we performed DNA sequencing for that region. We found four A1161G mutations and no A985G mutation in 35 newborns. Because the mutation was heterozygous and the disease was recessive, the effect of the mutation at protein level on the clinical situation could not be studied. The MCAD gene was cloned and mapped to chromosome 1p21, comprising 12 exons spanning 44 kb of DNA; 80% of hot spots are found on exon 11 for A985G transition, which results in the replacement of lysine by glutamate at codon 304. A total of 26 different mutations have been identi®ed in the MCAD gene but none of these mutations (other than A985G) was counted more often than 1% in variant alleles. However, in our preliminary study, the A1161G mutation was found in 11.4% of the Turkish population, it had not been previously reported in other nations. The results of the present study ®t with previous reports that MCAD de®ciency is a common disorder in non-Turkish Caucasians, and quite rare among Japanese [Nagao, 1996.]. Therefore, newborn mass screening for MCAD de®ciency using this method would not be practical in Turkey. However, it still seems necessary to investigate a child with fatty acid oxidation disorder for the presence of MCAD de®ciency, using both biochemical and molecular genetic methods.

The Distribution of Exon 3-Deleted/Full-Length Growth Hormone Receptor Polymorphism in the Turkish Population

Objective: The exon 3-deleted/full-length (d3/fl) growth hormone receptor (d3/fl-GHR) polymorphism has been associated with responsiveness to GH therapy in some children and also with adult height variation in the general population. We aimed to evaluate the distribution of d3/fl-GHR polymorphism in a Turkish population. Methods: The study included 477 (54 females/423 males) healthy adults with a mean±SD age of 31.1±9.0 years (range: 18-57). Height and body mass index (BMI) were expressed as standard deviation score (SDS) according to national standards. All adults had normal height and BMI SDSs (between -2 and +2). GHR exon 3 isoforms were studied by simple multiplex polymerase chain reaction method. Insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) values were also measured and expressed as SDS. Results: The distribution of the GHR exon 3 genotypes in the Turkish healthy adults was 35% (n=167) for fl/fl, 39% (n=186) for fl/d3, and 26% (n=124) for d3/d3. There was no difference between genders in GHR exon 3 genotypes. Frequencies of fl allele and d3 allele were 54.5% and 45.5%, respectively. There were no differences in height SDS and BMI SDS among the three d3/fl-GHR genotype groups. There was a significant difference in IGFBP-3 SDS between fl/fl and fl/d3 groups (p=0.022). Conclusions: This study presents the results of GHR polymorphism in a Turkish population as a reference for further studies. The distribution was similiar to European populations. There were no correlations between GHR isoforms and height SDS or other clinical/biochemical characteristics of the individuals except for higher IGFBP-3 levels in the fl/d3 group as compared to the fl/fl group. Whether this finding implies an abnormality, needs further investigation. Conflict of interest:None declared.