Osman Demirhan

A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies

We present a patient with acromesomelic chondrodysplasia and genital anomalies caused by a novel homozygous mutation in BMPR1B, the gene coding for bone morphogenetic protein receptor 1B. The 16 year old girl, the offspring of a multiconsanguinous family, showed a severe form of limb malformation consisting of aplasia of the fibula, severe brachydactyly, ulnar deviation of the hands, and fusion of carpal/tarsal bones. In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism. Mutation analysis of BMPR1B revealed a homozygous 8 bp deletion (del359–366). This mutation is expected to result in a loss of function and is thus different from the heterozygous missense mutations in BMPR1B recently shown to cause brachydactyly type A2 through a dominant negative effect. The patient’s skeletal phenotype shows an overlap with the clinical spectrum of the acromesomelic chondrodysplasias of the Grebe, Hunter-Thompson, and DuPan types caused by homozygous mutations in the gene coding for growth differentiation factor 5 (GDF5) which is a high-affinity ligand to BMPR1B. However, the phenotype described here differs from GDF5 associated chondrodysplasias because of the additional presence of genital anomalies and the distinct limb phenotype.

Cerebellar hypoplasia, with quadrupedal locomotion, caused by mutations in the very low-density lipoprotein receptor gene

The cerebellum is the primary motor coordination centre of the central nervous system. Lesions or congenital defects of the cerebellum cause incoordination of the muscles resulting in irregular gait and falling. Recently, we reported a large family with cerebellum hypoplasia and quadrupedal locomotion as a recessive trait, which we mapped to chromosome 17p13. We identified one additional family with the same condition and mapped the underlying gene to a 14-cM interval on chromosome 9ptel using a genome-wide linkage approach. Sequencing of candidate genes identified a homozygous frameshift mutation in the very low-density lipoprotein receptor (VLDLR) gene in all affected individuals. The association of cerebellar hypoplasia with mutations in VLDLR has been reported previously in the Hutterite population and in a family from Iran. However, quadrupedal locomotion was never observed indicating that environmental factors play a major role in the pathogenesis of this form of locomotion.

Chromosome aberrations in a schizophrenia population

Cytogenetic abnormalities with schizophrenia may provide a valuable clue to the identification of target loci and successful search for major genes. We have performed chromosomal examinations by using the GTG banding technique on 134 schizophrenics. In 43 patients (32%), random numerical and structural aberrations were detected. Structural aberrations predominated and usually consisted of deletions and inversion of various chromosomes. Numerical changes were present in one or two cells in 14 cases including trizomy 21, marker and acentric chromosomes, and 47,XXY. The seven cases with pericentric inversion and enlargement of the heterochromatin region of chromosome 9 (inv(9); 9qh+) were observed in the study. The incidence (5.2%) of inv(9) and 9qh+ in our schizophrenic patients were found higher than the general population, suggesting that a susceptibility locus for schizophrenia may be located at pericentromeric region of chromosome 9. Our study have detected 1q21, 7q23, inv(9), 9qh+, 11q23, 21q22, 22q11-13 and Xp11-q13 suggested that these chromosomal lesions are prevalent in schizophrenics. The reason for this might be that these anomalies increase risk for schizophrenia in a relatively nonspecific way, such as contributing to disruption of normal embryogenesis of the nervous system.

Cerebellar hypoplasia and quadrupedal locomotion in humans as a recessive trait mapping to chromosome 17p

Background: Congenital hereditary non-progressive hypoplasia of the cerebellum is a rare condition, frequently associated with other neuropathology such as lissencephaly. Clinically, the condition is associated with variable degrees of mental retardation, microcephaly, seizures, and movement disorders due to ataxia. In severe cases, patients are unable to ambulate independently, but nevertheless do use bipedal locomotion. Methods and Results: Here we present a family with seven affected members, five of whom never learned to walk on two legs but have fully adapted to quadrupedal palmigrade locomotion. These subjects show signs of cerebellar ataxia and are mentally retarded. MRI analysis demonstrated hypoplasia of the cerebellum and the cerebellar vermis as well as a small nucleus dentatus and a thin corpus callosum but no other malformations. We show, by a genome-wide linkage scan, that quadrupedal locomotion is a recessive trait linked to chromosome 17p. Conclusions: Our findings have implications for understanding the neural mechanism mediating bipedalism, and, perhaps, the evolution of this unique hominid trait.

The genotoxic effect of nicotine on chromosomes of human fetal cells: The first report described as an important study

Context: Recent studies have suggested a direct contribution of nicotine − the addictive component of tobacco and tobacco smoke − to human carcinogenesis, and it remains the most common harmful substance to which pregnant women are exposed. Also, it has deleterious effects on the fetus. The sperm of smoking fathers and newborns of smoking mothers have elevated frequencies of chromosome translocations and DNA strand breaks. Objective: We tried to understand the genotoxic effect of nicotine in pregnancies of active or passive smoking mothers. For this reason, we provide the evidence that nicotine exposure in vitro has detrimental effects on fetal cells. Materials and methods: We examined the effect of nicotine sulphate on amniotic cells by designing an experimental setting consisting fetal cells grown in nicotine containing medium (25 ng/mL) in study group and fetal cells grown in control medium, which did not contain nicotine. Results: According to our findings, there is a significant difference of chromosomal aberrations (CAs) between nicotine containing medium grown cells and control medium grown cells, determined by the χ2 test (P <0.001). We found CAs in 21.5% of cells analyzed. The 19.4% of the all cells had numerical aberrations. Chromosomes 21, 22, 8, 15 and 20 related numerical abnormalities were found to be the most frequent numerical abnormalities. Conclusion: Results of this study confirm that the nicotine leads to significant direct genotoxic effects in human fetal cells in vitro. We speculate that there is an association between prenatal exposure to cigarette smoke and in utero aneuploidies.

Chromosomal fragile sites in schizophrenic patients

Schizophrenia is a common and complex mental disorder. Cytogenetic and molecular studies have shown that genetic factors play an important role in the etiology of schizophrenia. As a preliminary step in the search for chromosomal location of a susceptible gene predisposing to schizophrenia, cytogenetic screening of patients might be useful. Therefore, this report is aimed at studying the relationship between chromosomal fragile sites (FS) (gaps, breaks, triradial figures, and several rearrangements) and the etiology of schizophrenia. Because of this, we compared the frequencies of folate-sensitive FS from schizophrenic patients and normal individuals in short-term whole-blood cultures. The rate of FS expression in the patients was considerably higher than in the controls. We determined 15 common FS (cFS) (1q21, 1q32, 2q21, 2q31, 3p14, 4q31, 5q31, 6q21, 6q26, 7q22, 7q32, 10q22, 13q32, Xp22, and Xq22), six rare FS (rFS) (6p21, 8q22, 11q23, 12q24, 16q22, and Xq26), and two previously unknown FS (3p25 and 5q22). Among these expressed FS, there was a significantly higher frequency of 12 FS at 2q31, 3p25, 3p14, 5q31, 6q21, 7q22, 7q32, 10q22, 11q23, 12q24, Xq22, and Xq26 in patient group than in controls by x2-test (P between 0.0001 to 0.036). Sites 3p14, 5q31, and 7q22 were also the most frequently observed cFS. Males exhibited twice as many FS as females, but no age effects were observed. The potential relationship between increased FS frequency and the occurrence of schizophrenia in these patients is discussed.

Cytogenetic effects of ethanol on chronic alcohol users.

AIM Alcoholism is a significant public health problem that is also associated with a complex genetic trait. Fragile sites (FS) are potentially informative endpoints for the study of clinical disorders. We aimed to find chromosomal damages in chronic alcohol users for the purpose of finding the correlation between alcohol and chromosomal anomalies. METHODS The potential roles/effects of ethanol on chromosome(s) were assessed in this study by investigating its cytotoxic effects in lymphocyte cultures from chronic alcoholics and controls. RESULTS Alcoholics revealed a significantly higher frequency of FS and chromosomal aberrations (CA), and the FS clusters in specific chromosomal regions: 1q12, 1q21, 1q32, 2p13, 2q21, 2q31, 3p14, 3p25, 3q21, 4q21, 4q31, 5q31, 6p21, 7q22, 7q32, 9q13, 9q22, 10q22, 11q23, and 12q13. We also observed a significantly greater number of numerical and structural CA in alcoholics. The most frequent exchange types were deletions and polymorphic variations. CA could be due to the cumulative effect of both alcohol and smoking. The loci 1q12, 3p25, 4q31, 6p21, and 12q13 were not reported previously in alcoholics and may be hot spots for alcoholism. The overall FS frequencies were not statistically different between smoker and non-smoker controls, but smoking significantly increased the expression of 1p36, 3q21, and 5p15 sites. These sites have important clinical significance. CONCLUSIONS Chronic alcohol abuse and the smoking habit can lead to chromosome damages that are especially influential on oncogenic regions, which may persist for a long time, and constitute a relevant factor of risk for the development of neoplasias.

Cytogenetic study of recurrent miscarriages and their parents.

There is substantial evidence that genetic alterations are contributing factors to the risk for recurrent miscarriages. This study was conducted to determine the frequency and contribution of chromosomal abnormalities in miscarriages and in couples with recurrent miscarriages. We studied a total of 41 miscarriages and their parents with a history of 2–11 recurrent miscarriages. Chromosomal analysis from chorionic villus sampling (CVS) and fetal tissues were performed according to standard cytogenetic methods using G-banding technique. Major chromosomal aberrations and polymorphic variants were found in 51 and 4.8%, respectively. The chromosomal abnormalities were structural (34.4%) and numerical (65.1%) of which 26.1, 21.7, 8.7 and 8.7% were fetal sex aneuploid, triploid, mosaics and trisomic, respectively. Unbalanced and balanced rearrangements were found in 17.2 and 8.6% of all abnormalities, respectively. Major chromosomal abnormalities in couples were seen in 4.9%. The chromosomal abnormalities associated with pregnancy losses and recurrent miscarriages are mostly numerical ones. The incidence of balanced translocations found here is 4.9% which is near to the mode (about 3–6%) observed in the previous studies. Those frequencies are greater than in the general population (0.3%). This indicates that balanced translocations, seen in parents, have some importance in causing miscarriage. The major parental chromosomal aberrations are significantly associated with fetal wastage. Mosaicism should be taken into account for cytogenetic analyses of pregnancy losses. Thus, cytogenetic analyses should be recommended in couples with recurrent miscarriages, when clinical data fail to clarify the cause.

Chromosomal fragile site expression in Turkish psychiatric patients

Chromosomal aberrations associated with psychiatric disorders may suggest regions in which to focus a search for genes predisposing to psychosis by a linkage strategy. Identification of these may be especially important given the unknown pathophysiology and the probable genetic heterogeneity of psychiatric disorders. In this study, the frequencies of folate sensitive fragile sites (FS) were compared among psychiatric disorders (e.g., schizophrenia, bipolar disorder, and other psychosis) and normal individuals. The rate of FS expression in the patients was considerably higher than in the controls. Sites 1p22, 1q21, 1q32, 2q31, 3p14, 3p25, 5q22, 5q31, 6p21, 6q21, 6q25, 7q22, 7q32, 8q22, 10q21, 11q23, 12q24, 13q32, 14q24, 16q22, 17q21, Xp22 and Xq26 were expressed more frequently in the patients. Thirty possible relevant chromosomal sites were identified in schizophrenia: 1q21, 1q32, 2p13, 2q21, 3p14, 3p25, 3q21, 5q22, 5q31, 6p21, 6q25, 6q26, 7q21, 7q22, 7q32, 8q22, 9q21, 10q21, 11q23, 12q24, 13q32, 14q24, 16q22, 17q21, Xp22, Xq22, and Xq26. Possible relevant sites were also identified in bipolar disorder: sites 1p36, 1q21, 1q32, 3p14, 3p25, 5q31, 7q22, 7q32, 11q23, 12q24, 13q32, 14q24, Xp22, and Xq26. Sites in the other psychosis group were: 1p22, 1p32, 1p36, 1q21, 1q32, 2q31, 3p14, 3p25, 5q31, 6p21, 6q21, 6q25, 6q26, 7q22, 7q32, 8q22, 10q21, 11q23, 12q13, 12q24, 13q32, 16q22, 16q24, 17q21 and Xq26. Among patient groups, there were significant differences in bands 1p32, 2p13, 2q21, 2q31, 3p14, 3p25, 5q31, 6q21, 6q26, 7q22, 7q32, 9q21, 11qq23, 12q13, 12q24, 16q24, and Xq22 between schizophrenic and bipolar patients. These regions were more frequently expressed in schizophrenic patients than in bipolar patients. The 1p22, 1p32, and 16q24 regions were significantly more frequently expressed in the other psychosis group than in the bipolar group. These interesting regions, which may harbor important genes for psychosis, have produced strong support for linkage in the majority of genome scan projects.

Chromosomal analyses of 1510 couples who have experienced recurrent spontaneous abortions

In this retrospective study, karyotype results of 1510 couples with a history of recurrent spontaneous abortion were evaluated. The study was conducted at Balcalı Hospital in Adana region of Turkey. For all cases, peripheral blood lymphocytes were cultured for chromosome study using the standard method. Chromosome aberrations were detected in 62 couples (4.1% of all couples). At an individual level, chromosome aberrations were found in a total of 65 cases (41 females and 24 male cases), with structural chromosomal aberrations in 58 cases including balanced translocations in 30 cases, Robertsonian translocations in 12 cases, deletions in seven cases, inversions in nine cases and numerical chromosome aberrations in seven cases. The results of the study indicated that structural aberrations, particularly translocations, were the most common type of aberration observed among couples who had experienced recurrent spontaneous abortions and that these couples might benefit from cytogenetic analyses.