Identification of a SLC19A2 nonsense mutation in Persian families with thiamine-responsive megaloblastic anemia

This is an Open Access article. A definitive version was published in Gene, Vol.519, issue 2, (2013) doi: 10.1016/j.gene.2013.02.008.Thiamine-responsive megaloblastic anemia (TRMA) is an autosomal recessive syndrome characterized by early-onset anemia, diabetes, and hearing loss caused by mutations in the SLC19A2 gene. We studied the genetic cause and clinical features of this condition in patients from the Persian population. A clinical and molecular investigation was performed in four patients from three families and their healthy family members. All had the typical diagnostic criteria. The onset of hearing loss in three patients was at birth and one patient also had a stroke and seizure disorder. Thiamine treatment effectively corrected the anemia in all of our patients but did not prevent hearing loss. Diabetes was improved in one patient who presented at the age of 8months with anemia and diabetes after 2months of starting thiamine. The coding regions of SLC19A2 were sequenced in all patients. The identified mutation was tested in all members of the families. Molecular analyses identified a homozygous nonsense mutation c.697C>T (p.Gln233*) as the cause of the disease in all families. This mutation was previously reported in a Turkish patient with TRMA and is likely to be a founder mutation in the Persian population

Prenatal exposure to maternal cigarette smoking, amygdala volume, and fat intake in adolescence

Context : Prenatal exposure to maternal cigarette smoking is a well-established risk factor for obesity, but the underlying mechanisms are not known. Preference for fatty foods, regulated in part by the brain reward system, may contribute to the development of obesity. Objective : To examine whether prenatal exposure to maternal cigarette smoking is associated with enhanced fat intake and risk for obesity, and whether these associations may be related to subtle structural variations in brain regions involved in reward processing. Design : Cross-sectional study of a population-based cohort. Setting : The Saguenay Youth Study, Quebec, Canada. Participants : A total of 378 adolescents (aged 13 to 19 years; Tanner stage 4 and 5 of sexual maturation), half of whom were exposed prenatally to maternal cigarette smoking (mean [SD], 11.1 [6.8] cigarettes/d). Main Outcome Measures : Fat intake was assessed with a 24-hour food recall (percentage of energy intake consumed as fat). Body adiposity was measured with anthropometry and multifrequency bioimpedance. Volumes of key brain structures involved in reward processing, namely the amygdala, nucleus accumbens, and orbitofrontal cortex, were measured with magnetic resonance imaging. Results : Exposed vs nonexposed subjects exhibited a higher total body fat (by approximately 1.7 kg; P = .009) and fat intake (by 2.7%; P = .001). They also exhibited a lower volume of the amygdala (by 95 mm3; P < .001) but not of the other 2 brain structures. Consistent with its possible role in limiting fat intake, amygdala volume correlated inversely with fat intake (r = −0.15; P = .006). Conclusions : Prenatal exposure to maternal cigarette smoking may promote obesity by enhancing dietary preference for fat, and this effect may be mediated in part through subtle structural variations in the amygdala

Genome-wide Association Study of Fat intake in Adolescence

Dietary preference for fat, which increases risk for obesity, is a complex behavior regulated in part by the brain-reward system. We conducted a genome-wide association study (GWAS) to search for loci associated with relative fat intake in 598 adolescents (12-18 years) who were recruited from the French-Canadian founder population. The GWAS identified a locus in the μ-opioid receptor gene (OPRM1, rs2281617, p=5.2x10-6), which encodes a receptor expressed in the brain-reward system and which has been shown previously to modulate fat preference in animals. The minor OPRM1 allele appeared to have a “protective” effect: it was associated with lower fat intake and lower body-fat mass, In addition, OPRM1 was associated with relative fat intake in an independent sample of 490 young adults. In summary, OPRM1 may modulate dietary preference for fat and hence the risk for obesity. Further studies are required to confirm our findings.MAS

The effect of Group Cognitive-Behaviour Therapy in combination with Pharmacotherapy on Mania and Depression Symptoms and Awareness of warming signs of relapse in patients with Bipolar Disorder

"n&nbsp;Objective:&nbsp;This research has been done according to the cognitivebehavioral theories and biochemical model in order to evaluate the efficiency of Group Cognitive-Behavior Therapy in combination with Pharmacotherapy on Mania and Depression Symptoms and Awareness of warning signs of relapse in patients with Bipolar Disorder. "n "nMethods:In this study with the experimental pretest- posttest- follow up plan , 30 women suffering from bipolar disorder, randomly assigned to receive either the group cognitive-behavior therapy (experimental group, n=15) or usual treatment (control group, n=15);and were follow-up for a six months. patients in both groups were prescribed standard Pharmacotherapy. First all subjects were put to a pretest in equal conditions with measures of scale 2 and 9 of MMPI Test, and warning signs checklist. Then the experimental group received group cognitive-behavior therapy for 8 sessions in addition to their medication therapy. The control group only received medicine. At the end of the experiment, all subjects were tested under equal conditions. After completion of the treatment process, the subjects of both groups were supervised for 6 months. The findings of the study were analyzed by the statistical method of Multi-variable analysis of variance with repetitive measurements. "nResults:The findings showed that the group cognitive-behavior therapy had been significantly more efficient in reduction of mania symptoms {p=0/03} and increment of awareness of warning signs of relapse {p=0/00} in comparison with control group; but there is no significantly differences in depression symptoms between two groups. "nConclusion: The findings of this study suggest the beneficial effect of Group cognitive-behavior therapy in reducing of mania symptoms and increment of awareness of warning signs of relapse. Therefore, it can be used as a complementary treatment by clinician

Homozygosity Mapping and Whole Exome Sequencing Reveal a Novel Homozygous <i>COL18A1</i> Mutation Causing Knobloch Syndrome

<div><p>The aim of this study was to identify the genetic basis of a chorioretinal dystrophy with high myopia of unknown origin in a child of a consanguineous marriage. The proband and ten family members of Iranian ancestry participated in this study. Linkage analysis was carried out with DNA samples of the proband and her parents by using the Human SNP Array 6.0. Whole exome sequencing (WES) was performed with the patients’ DNA. Specific sequence alterations within the homozygous regions identified by whole exome sequencing were verified by Sanger sequencing. Upon genetic analysis, a novel homozygous frameshift mutation was found in exon 42 of the <i>COL18A1</i> gene in the patient. Both parents were heterozygous for this sequence variation. Mutations in <i>COL18A1</i> are known to cause Knobloch syndrome (KS). Retrospective analysis of clinical records of the patient revealed surgical removal of a meningocele present at birth. The clinical features shown by our patient were typical of KS with the exception of chorioretinal degeneration which is a rare manifestation. This is the first case of KS reported in a family of Iranian ancestry. We identified a novel disease-causing (deletion) mutation in the <i>COL18A1</i> gene leading to a frameshift and premature stop codon in the last exon. The mutation was not present in SNP databases and was also not found in 192 control individuals. Its localization within the endostatin domain implicates a functional relevance of endostatin in KS. A combined approach of linkage analysis and WES led to a rapid identification of the disease-causing mutation even though the clinical description was not completely clear at the beginning.</p></div

Coverage of sequencing reads in <i>COL18A1</i> including a 14 bp deletion (NM_130445.2:c.3825_3838del:p.Ser1276Alafs*9 (Exon 42) as seen on Alamut Viewer 2.2.0 (Upper panel).

<p>A loss of multiple strong ESEs is predicted due to the deletion (Lower panel).</p

Classification of the type of homozygous variants obtained by linkage analysis and whole exome sequencing.

<p>Classification of the type of homozygous variants obtained by linkage analysis and whole exome sequencing.</p

Homozygosity Mapping and Whole Exome Sequencing Reveal a Novel Homozygous <i>COL18A1 - Figure 3 </i> Mutation Causing Knobloch Syndrome

<p>a. Sanger sequencing of <i>COL18A1</i> mutation NM_130445.2:c.3825_3838del:p.Ser1276Alafs*9 (Exon 42) comparing a wild type sequence (top), homozygous deletion in index patient IV-1 (middle) and heterozygous deletion in father of the index patient (bottom). b. Conservation of the deleted nucleotides across various species. c. Alignment of three isoforms of <i>COL18A1</i> and endostatin. The highlighted region is deleted in patient IV-1.</p

Demanded interdisciplinary subjects for integration in medical education program from the point of view of graduated medical physicians and senior medical students: a nationwide mixed qualitative-quantitative study from Iran

Abstract Introduction This study aimed to detect interdisciplinary subjects for integration into the medical education program of Iran. Methods A qualitative-quantitative method was used. Firstly, interdisciplinary subjects demanded by medical graduates and senior medical students were defined by qualitative study. In the second stage, questionnaire was developed which based on the findings of qualitative stage, experts’ opinion and reviewing of the national general guide of professional ethics for medical practitioners. Questionnaire consisted of demographic, occupational and thirteen interdisciplinary items. These items consisted of social determinants of health, social and economic consequences of disease, social prescribing, physicians’ social responsibility, role of gender, racial, ethnic, social and economic issues in approach to patients, role of logic and mathematics in clinical decision-making, philosophy of medicine, maintaining work-life balance, self-anger management, national laws of medicine, religious law in medical practice, health system structure, and teamwork principles. Level and importance of knowledge and self-assessed educational needs were asked about each item. In the third stage, a national online survey was conducted. SPSS 25 was used for statistics. Results By content analysis of data in qualitative stage, 36 sub-themes and 7 themes were extracted. In the quantitative part, 3580 subjects from 41 medical universities across Iran participated in this study. 2896 (80.9%) were medical graduates and 684 (19.1%) were senior medical students. Overall, knowledge about interdisciplinary items was low to intermediate, while high to very high knowledge ranged from maximally 38.7% about socioeconomic consequences of disease to minimally 17.2% about social prescribing. Participants gave the most importance to the having knowledge about self-anger management (88.3%), maintaining work-life balance (87.2%) and social determinants of health (85.8%), respectively. However, national laws of medicine (77.6%), maintaining work-life balance (75.4%) and self-anger management (74%) were the first top three educational demands by participants. Conclusion This study revealed a low to moderate level of knowledge about interdisciplinary topics among both graduated medical physicians and senior medical students. These groups showed a strong demand and tendency to know and to be educated about these topics. These findings underscore the urgency for educational reforms to meet the interdisciplinary needs of medical professionals in Iran