Serap Emre

Two New Loci for Autosomal Recessive Ichthyosis on Chromosomes 3p21 and 19p12-q12 and Evidence for Further Genetic Heterogeneity

Autosomal recessive ichthyosis (ARI) includes a heterogeneous group of disorders of keratinization characterized by desquamation over the whole body. Two forms largely limited to the skin have been defined: lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE). A first gene for LI, transglutaminase TGM1, has been identified on chromosome 14, and a second one has been localized on chromosome 2. In a genomewide scan of nine large consanguineous families, using homozygosity mapping, two new loci for ARI were found, one for a lamellar form in a 6-cM interval on chromosome 19 and a second for an erythrodermic form in a 7.7-cM interval on chromosome 3. Linkage to one of the four loci could be demonstrated in more than half of 51 consanguineous families, most of them from the Mediterranean basin. All four loci could be excluded in the others, implying further genetic heterogeneity in this disorder. Multipoint linkage analysis gave maximal LOD scores of 11.25 at locus D19S566 and 8.53 at locus D3S3564.

The effect of zinc-supplemented bread consumption on school children with asymptomatic zinc deficiency

BACKGROUND Zinc deficiency has been seen in developing countries in which grain-based vegetable protein is consumed more often than animal protein. This study was done to emphasize the importance of zinc-fortified foods and to investigate bioavailability of zinc in zinc-fortified bread. METHODS Serum zinc concentrations in healthy 7- to 11-year-old school children were determined. In 24 of 101 children serum zinc concentrations were below 65 micrograms/ul. These 24 children with asymptomatic zinc deficiency were divided into two equal groups. The 12 children with low serum zinc concentrations received the zinc-fortified bread providing 2 mg/kg/day elemental zinc acetate for 90 days (zinc-supplemented group), whereas the other 12 children received the same quality bread with no zinc fortification (control group). RESULTS By the end of the period, the zinc-supplemented group had significantly higher serum and leukocyte zinc concentrations (p < 0.01) and the weight, serum albumin levels, and alkaline phosphatase increased (p < 0.01). Immune functions improved, evidenced by conversion of delayed hypersensitivity skin reactions. Zinc-fortified bread (2 mg/kg/day) caused no side effects or manifestations of zinc toxicity. CONCLUSIONS The results indicate that the bioavailability of zinc in the bread is satisfactory. The use of zinc-fortified bread was found to be an economical and readily accessible method to eliminate zinc deficiency and to prevent further occurrence.

Molecular analysis of Chanarin-Dorfman syndrome (CDS) patients: Identification of novel mutations in the ABHD5 gene

Chanarin-Dorfman syndrome (CDS) is an autosomal recessive metabolic disorder associated with congenital ichthyosis and a multisystemic accumulation of neutral lipids in various types of cells. Recently, mutations of the ABHD5 gene were identified as the cause of CDS. In this work, we carried out molecular analysis of the ABHD5 gene in 6 unrelated patients. We identified one previously reported mutation, N209X and two novel genetic alterations; a nonsense mutation (p.Y50X) and missense mutation (p.S73A).

Sister chromatid exchange in lymphocytes of patients with cancer of the larynx

The frequency of sister chromatid exchange (SCE) was studied in cultured peripheral lymphocytes from 15 untreated patients with carcinoma of the larynx and 10 healthy control subjects. Bromodeoxyuridine-incorporated chromosomes were treated with Hoechst 33258 and stained according to conventional methods. To measure SCE frequency, at least 15 mitoses per donor were evaluated. The SCE values were found to be higher in cancer cases than in control cases.

Molecular analysis of Turkish Gaucher disease patients: identification of novel mutations in glucocerebrosidase (GBA) gene.

Gaucher disease (GD) is the most frequent lysosomal glycolipid storage disorder due to autosomal recessive deficiency of acid beta-glucosidase and is characterized by the accumulation of glucocerebroside. In this work we carried out molecular analysis of the glucocerebrosidase gene (GBA) in 57 unrelated patients and the alleleic frequencies of gene mutations in Turkish patients are reported. The most prevalent are L444P and N370S accounting for 42% and 30% in our patients. We identified three novel genetic alterations: two missense changes S356F, L296V that are associated with the severe phenotype of type 1 GD. 303-305delCAC was identified in a homozygous state in one patient type 1 or type 3.

Chanarin-Dorfman syndrome: Genotype-Phenotype Correlation

Chanarin-Dorfman syndrome is an autosomal recessive lipid storage disease characterized by non-bullous congenital ichthyosiform erythroderma, and involvement of the liver, muscles and central nervous system due to a multisystemic accumulation of neutral lipids in various types of cells. Less than 100 affected individuals have been reported worldwide, the majority from the Mediterranean and Middle-East countries, especially Turkey. We present clinical and molecular data of four affected relatives with Chanarin-Dorfman syndrome homozygous for a N209X mutation in ABHD5, and provide a short review by comparing patients with N209X homozygous mutations to patients with other ABHD5 mutations. No major clinical differences exist between individuals with an N209X mutation and those with other mutations, which argues against a genotype/phenotype correlation.

Glucose-6-phosphatase gene mutations in Turkish patients with glycogen storage disease type Ia

Glycogen storage disease type Ia (GSD Ia; von Gierke Disease; McKusick 232200) is an autosomal recessive inborn error of metabolism resulting from the de¢ciency of microsomal glucose-6-phosphatase (G6Pase, EC 3.1.3.9), the enzyme catalysing the terminal step in gluconeogenesis and glycogenolysis. The human G6Pase gene is located on chromosome 17; its transcription unit spans 12.5 kb and is composed of ¢ve exons. The protein encoded by this gene contains 357 amino acids and is an endoplasmic reticulum (ER) membrane-associated protein containing an ER retention signal (KK) and possesses six putative membrane-spanning segments. The diagnosis of GSD Ia was established in 12 unrelated Turkish patients by demonstrating G6Pase de¢ciency in liver biopsy. Genomic DNAwas extracted from leukocytes of peripheral blood by a salting-out procedure. The ¢ve exons of the G6Pase gene and their £anking intron/exon junctions were ampli¢ed. The ampli¢ed fragments were separated on a 7% acrylamide gel and run at room temperature at 1000V in 1 TBE bu¡er for 5 h in order to analyse single-strand conformation changes. The fragments that showed an aberrant migration pattern were subject to direct sequence analysis with an automated sequencer (ABI A310). We have analysed the G6Pase gene of all 12 patients. Two mutations were found: R83C (14 of the 24 alleles) and W77R (10 of the 24 alleles). All patients were homozygous for one or other of these two mutations. There was parental consanguinity in all our families. The R83C mutation has an allele frequency gradient of 93% in Jewish and 25.2% in caucasian patients in the United States and north-west Europe (Rake et al 2000). A previous study indicated an allele frequency of 60% in Turkish patients, including one that lived in Germany (Hˇner et al 1998). In the present study, the allele frequency of the R83C mutation is 58.3% (14/24). Thus, this mutation is quite common in the patients of Turkish origin and ¢ts the gradient of southern European patients (48%). The second mutation, W77R, was ¢rst found in a French patient (Chevalier-Prost et al 1996). This mutation is located within the second transmembrane helix of glucose-6-phosphatase. The structural requirement of the transmembrane helices J. Inherit. Metab. Dis. 24 (2001) 881^882 # SSIEM and Kluwer Academic Publishers. Printed in the Netherlands.

Lipid Droplets in Health and Disease

Lipids are essential building blocks synthesized by complex molecular pathways and deposited as lipid droplets (LDs) in cells. LDs are evolutionary conserved organelles found in almost all organisms, from bacteria to mammals. They are composed of a hydrophobic neutral lipid core surrounding by a phospholipid monolayer membrane with various decorating proteins. Degradation of LDs provide metabolic energy for divergent cellular processes such as membrane synthesis and molecular signaling. Lipolysis and autophagy are two main catabolic pathways of LDs, which regulate lipid metabolism and, thereby, closely engaged in many pathological conditons. In this review, we first provide an overview of the current knowledge on the structural properties and the biogenesis of LDs. We further focus on the recent findings of their catabolic mechanism by lipolysis and autophagy as well as their connection ragarding the regulation and function. Moreover, we discuss the relevance of LDs and their catabolism-dependent pathophysiological conditions.

Loss of Heterozygosity in the VNTR Region of Intron 1 of P53 in two Retinoblastoma Cases

Loss of heterozygosity (LOH) was studied in 10 primary retinoblastoma tumors in the VNTR region of intron 1 in p53 gene by the polymerase chain reaction. To our knowledge mutations have not been reported in the p53 gene in retinoblastoma primary tumors. Heterozygosity was found at this region in 5 of 10 cases. Two pathology paraffin block samples showed loss of heterozygosity.

SCE frequency of herpes simplex virus type I infected cells.

The effects of herpes simplex virus type I (HSV-I) on SCE frequencies in human lymphocytes in vitro were investigated. SCE frequencies in controls (mean +/- 1SD 5.2 +/- 1.6) and in cells exposed to the virus for 3 and 6 h (mean +/- 1SD 5.3 +/- 1.6 and 5.8 +/- 1.6 respectively) were about the same. However, cells infected for 9 to 24 h showed a significant increase of SCE frequencies (p < 0.05).