Sukru Palanduz

Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes

Recently, deletions encompassing the nuclear receptor binding SET-Domain 1 (NSD1) gene have been described as the major cause of Japanese patients with the Sotos syndrome, whereas point mutations have been identified in the majority of European Sotos syndrome patients. In order to investigate a possible phenotype–genotype correlation and to further define the predictive value of NSD1 mutations, we performed mutational analysis of the NSD1 gene in 20 patients and one familial case with Sotos syndrome, five patients with Weaver syndrome, six patients with unclassified overgrowth/mental retardation, and six patients with macrocephaly/mental retardation. We were able to identify mutations within the NSD1 gene in 18 patients and the familial case with Sotos syndrome (90%). The mutations (six nonsense, eight frame shifts, three splice site, one missense, one in-frame deletion) are expected to result in an impairment of NSD1 function. The best correlation between clinical assessment and molecular results was obtained for the Sotos facial gestalt in conjunction with overgrowth, macrocephaly, and developmental delay. In contrast to the high mutation detection rate in Sotos syndrome, none of the patients with Weaver syndrome, unclassified overgrowth/mental retardation and macrocephaly/mental retardation, harbored NSD1 mutations. We tested for large deletions by FISH analysis but were not able to identify any deletion cases. The results indicate that the great majority of patients with Sotos syndrome are caused by mutations in NSD1. Deletions covering the NSD1 locus were not found in the patients analyzed here.

Brachydactyly type C caused by a homozygous missense mutation in the prodomain of CDMP1

Brachydactyly type C (BDC) is characterized by shortening of the middle phalanges of the index, middle, and little finger with hyperphalangy, usually of the index and middle finger. Heterozygous mutations of the cartilage derived morphogenetic protein‐1 (CDMP1) resulting in a loss of function have been reported in BDC. We here describe a large kindred with a semi‐dominant form of BDC and pronounced ulnar deviation of the second and third digits. In this family a novel homozygous missense mutation was identified (517A > G) changing methionine to valine at amino acid position 173. The mutation is located within a highly conserved seven amino acid region of the prodomain of CDMP1. Hand radiographs of heterozygous mutation carriers showed mild shortening of the metacarpals IV and V; a finding confirmed by the analysis of their metacarpophalangeal profiles (MCPPs). The mutation described here points toward an important function of the prodomain for the folding, secretion, and availability of biologically active CDMP1.

Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis

Pachydermoperiostosis, or primary hypertrophic osteoarthropathy (PHO), is an inherited multisystem disorder, whose features closely mimic the reactive osteoarthropathy that commonly accompanies neoplastic and inflammatory pathologies. We previously described deficiency of the prostaglandin‐degrading enzyme 15‐hydroxyprostaglandin dehydrogenase (HPGD) as a cause of this condition, implicating elevated circulating prostaglandin E2 (PGE2) as causative of PHO, and perhaps also as the principal mediator of secondary HO. However, PHO is genetically heterogeneous. Here, we use whole‐exome sequencing to identify recessive mutations of the prostaglandin transporter SLCO2A1, in individuals lacking HPGD mutations. We performed exome sequencing of four probands with severe PHO, followed by conventional mutation analysis of SLCO2A1 in nine others. Biallelic SLCO2A1 mutations were identified in 12 of the 13 families. Affected individuals had elevated urinary PGE2, but unlike HPGD‐deficient patients, also excreted considerable quantities of the PGE2 metabolite, PGE‐M. Clinical differences between the two groups were also identified, notably that SLCO2A1‐deficient individuals have a high frequency of severe anemia due to myelofibrosis. These findings reinforce the key role of systemic or local prostaglandin excess as the stimulus to HO. They also suggest that the induction or maintenance of hematopoietic stem cells by prostaglandin may depend upon transporter activity. Hum Mutat 33:1175–1181, 2012.

Sister chromatid exchanges in lymphocytes of nuclear medicine physicians

OBJECTIVE The aim of this study was to assess whether occupational exposure to chronic, low doses of Iodine 131 (I-131) and Technetium 99m (Tc-99m) may lead to genotoxicity. Medical personnel occupied in nuclear medicine departments are occupationally exposed to low doses of I-131 and Tc-99m. The determination of the frequency of sister chromatid exchanges (SCEs) and of cells with a high frequency of SCEs (HFC) is considered to be a sensitive indicator for detecting genotoxic potential of mutagenic and carcinogenic agents. Therefore, we examined peripheral lymphocytes from nuclear medicine physicians for the presence of both SCE and HFC. METHODS Sixteen exposed nuclear medicine physicians (non-smokers) were compared to 16 physicians (non-smokers) who had not been exposed to chemical or physical mutagens in their usual working environment at the same hospital. RESULTS A statistically significant difference was found between SCE frequencies and HFC percentages measured in lymphocytes from the exposed and control groups. CONCLUSIONS The present observation on the effect of chronic low doses of I-131 and Tc-99m indicates the possibility of genotoxic implications of this type of occupational exposure. Hence, the personnel who work in nuclear medicine departments should carefully apply the radiation protection procedures and should minimize, as low as possible, radiation exposure to avoid possible genotoxic effects.

A novel locus for syndromic chronic idiopathic intestinal pseudo-obstruction maps to chromosome 8q23–q24

Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a rare and severe clinical syndrome characterized by symptoms and signs of intestinal occlusion, in the absence of any mechanical obstruction of the gut lumen. In the attempt to identify the genetic basis of CIIP, we analyzed a Turkish pedigree with a high degree of consanguinity in which three siblings presented with a syndromic form of CIIP. All affected family members were characterized by recurrent, self-limiting subocclusive episodes, long-segment Barrett esophagus, and a variety of minor cardiac valve or septal defects. In some patients full-thickness intestinal biopsy samples were obtained and tissues were processed for immunohistochemistry using antibodies to different markers of the intestinal neuromuscular tract. Full-thickness biopsies of the gut wall showed abnormalities of both the neural and muscular components suggesting an underlying intestinal neuro-myopathy. Blood samples were collected for DNA extraction from each available family member and DNAs were genotyped using 382 microsatellites spanning the entire genome with the aim to take advantage of the homozygosity mapping approach. Linkage analysis identified a new syndromic locus on chromosome 8q23–q24 (multipoint LOD score=5.01). Our data strongly support the presence of a new genetic locus associated with CIIP, long-segment Barrett esophagus, and cardiac involvement on chromosome 8.

Clinical and molecular characterization of two adults with autosomal recessive Robinow syndrome

Autosomal recessive Robinow syndrome is caused by mutations in ROR2 and is characterized by short stature, mesomelic limb shortening, brachydactyly, vertebral abnormalities, and a characteristic “fetal face” dysmorphology. We report the clinical and molecular studies on two adults with this condition. Besides typical skeletal and facial features, one patient developed hydronephrosis, nephrocalcinosis, and renal failure. The second patient had characteristic skeletal manifestations including severe spinal involvement and showed endocrinological abnormalities including elevated gonadotropic hormones. The facial phenotype in both patients remained distinctive into adulthood. Analysis of the ROR2 gene revealed a homozygous c.1937_1943delACAAGCT mutation in Patient 1, and compound heterozygosity for c.355C > T (p.R119X). and c.550C > T (p.R184C) in Patient 2.

WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.

Acute Wood or Coal Exposure with Carbon Monoxide Intoxication Induces Sister Chromatid Exchange

Objective: The object of this study was to investigate the genotoxic effect of acute overexposure to combustion products originating from coal or wood stoves in patients presenting with acute carbon monoxide intoxication. Study Design: In a prospective study, we analyzed the frequency of sister chromatid exchange and the carboxyhemoglobin concentration in 20 consecutive patients without a history of smoking or drug use who had been treated in the Emergency Care Unit of Istanbul Medical Faculty due to acute carbon monoxide intoxication. All of these cases were domestic accidents due to dysfunctioning coal or wood stoves. The results were compared with a control group of 20 nonsmoking, nondrug-using healthy individuals matched for age, sex, and absence of other chemical exposure. Results: The mean sister chromatid exchange frequency per metaphase was significantly higher in the study group compared to the control group: 8.11±2.39 vs. 6.33±1.60 (p=0.008). We found that there was no positive correlation between the blood carboxyhemoglobin concentration and sister chromatid exchange frequency. Conclusions: These results suggest that acute exposure to combustion products of wood or coal is genotoxic to DNA. Potential causes of genotoxicity include known mutagenic compounds present in coal or wood smoke and ash, oxygen radicals formed during combustion, as well as hypoxic and reperfusion injury mechanisms initiated by carbon monoxide intoxication. Additional studies on separate carbon monoxide exposure from smoke and ash are needed to understand individual genotoxic contributions and mechanisms.

Investigation of Arg399Gln and Arg194Trp polymorphisms of the XRCC1 (x-ray cross-complementing group 1) gene and its correlation to sister chromatid exchange frequency in patients with chronic lymphocytic leukemia.

Polymorphisms of the x-ray repair cross-complementing group 1 (XRCC1) gene have been reported to be associated with various forms of cancer. We evaluated the possible effects of the Arg194Trp and the Arg399Gln polymorphisms on the risk for chronic lymphocytic leukemia (CLL) in 73 patients and 50 controls. We also analyzed their relation to frequency of sister chromatid exchange (SCE). With respect to codon 194, the allelic frequency of the Arg194Trp polymorphism did not significantly differ between the 2 groups. The proportion of individuals carrying the Arg194Trp polymorphism was not different in the 2 groups. With respect to codon 399, the proportion of the individuals carrying the Arg399Gln allele (90% vs 62%; p=0.000; odds ratio [OR], 5.779; 95% confidence interval [CI], 2.2-15.183) and the allelic frequency of the Arg399Gln polymorphism (56% vs 36%; p=0.002; OR, 2.278; 95% CI, 1.350-3.843) was significantly higher in the patient group. The frequency of the Arg/Gln genotype was significantly higher in the patient group (68.50% vs 52%; p=0.049; OR, 2.007; 95% CI, 0.955-4.217). The mean SCE frequency in the patient group was significantly higher (9.2±4 vs 7.5±2; p=0.02). When different compound genotypes were compared, the coexistence of Arg/Arg genotype in codon 194 with Arg/Arg genotype in codon 399 was significantly more frequent in the control group (30% vs 9%; p=0.004; OR, 0.247; 95% CI, 0.092-0.664). Within the patient group, SCE frequency did not differ between patients with various genotypes. The Arg399Gln polymorphism may be etiologically associated with CLL; however, it does not seem to increase SCE frequency.

Loss of heterozygosity at chromosome 14q is associated with poor prognosis in head and neck squamous cell carcinomas

Purpose and methodsLoss of heterozygosity (LOH) in a chromosomal location indicates the presence of an inactivated tumor suppressor gene (TSG). Inactivation of TSG has a functional role in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC). Based on the recent evidences of a putative TSG on chromosome 14, we examined LOH on chromosome 14q using eight polymorphic microsatellite markers in 50 cases of HNSCCs.ResultsThree regions were detected to have a high LOH rate which included 14q21.2-22.3 (42.5%), 14q31 (55%), and 14q32.1 (37%). The correlation between LOH and clinicopathological findings was investigated through statistical analyses. A strong correlation was observed between the highest LOH marker and the overall and disease-free survival.ConclusionsThe results suggest that the distal part of chromosome 14 may host a TSG that may lead to the development and/or progression of HNSCCs. Several genes such as CHES1, BMP4, SAV, and PNN have arisen as candidate tumor suppressors in the region.