Deep sequencing reveals 50 novel genes for recessive cognitive disorders.

Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function.

Autosomal recessive mental retardation: homozygosity mapping identifies 27 single linkage intervals, at least 14 novel loci and several mutation hotspots.

Mental retardation (MR) has a worldwide prevalence of around 2% and is a frequent cause of severe disability. Significant excess of MR in the progeny of consanguineous matings as well as functional considerations suggest that autosomal recessive forms of MR (ARMR) must be relatively common. To shed more light on the causes of autosomal recessive MR (ARMR), we have set out in 2003 to perform systematic clinical studies and autozygosity mapping in large consanguineous Iranian families with non-syndromic ARMR (NS-ARMR). As previously reported (Najmabadi et al. in Hum Genet 121:43-48, 2007), this led us to the identification of 12 novel ARMR loci, 8 of which had a significant LOD score (OMIM: MRT5-12). In the meantime, we and others have found causative gene defects in two of these intervals. Moreover, as reported here, tripling the size of our cohort has enabled us to identify 27 additional unrelated families with NS-ARMR and single-linkage intervals; 14 of these define novel loci for non-syndromic ARMR. Altogether, 13 out of 39 single linkage intervals observed in our cohort were found to cluster at 6 different loci on chromosomes, i.e., 1p34, 4q27, 5p15, 9q34, 11p11-q13 and 19q13, respectively. Five of these clusters consist of two significantly overlapping linkage intervals, and on chr 1p34, three single linkage intervals coincide, including the previously described MRT12 locus. The probability for this distribution to be due to chance is only 1.14 × 10(-5), as shown by Monte Carlo simulation. Thus, in contrast to our previous conclusions, these novel data indicate that common molecular causes of NS-ARMR do exist, and in the Iranian population, the most frequent ones may well account for several percent of the patients. These findings will be instrumental in the identification of the underlying genes.

Improvement Efficacy of Influenza Nanovaccine in Combination with Hemokinin-1 Molecular Adjuvant.

BACKGROUND: H9N2 avian influenza viruses have the potential to become the next human pandemic threat and next generation vaccine technologies are needed. Current studies introduce nanoparticles as a proper vaccine delivery vehicle for induction of protective immunity. In this study, the efficacy of chitosan nanoparticle-based H9N2 influenza vaccine with and without hemokinin-1 (HK-1) as a molecular adjuvant to induce protective immunity against the virus was examined. METHODS: The H9N2 antigen was prepared in MDCK cells and inactivated with formalin. The inactivated antigen alone and in combination with HK-1 was encapsulated into chitosan nanoparticles. Groups of BALB/c mice received chitosan nanoparticle-based H9N2 antigen alone or in combination with HK-1 in a prime/boost platform via eye drop method. To evaluate the efficacy of the adjuvanted-nanovaccine candidate, systemic antibody responses were compared among the groups of animals. RESULTS: Serological analysis indicated that mice receiving the HK-1/H9N2 nanoparticles formulation induced higher antibody titers that were sustained until the end of experiment. However, in the immunized mice, influenza specific antibody titers were comparable to that in the animals which were immunized either with inactivated antigen alone or the H9N2 nanoparticles without HK-1 adjuvant. CONCLUSION: The data demonstrate the synergy between HK-1 as an adjuvant and chitosan nanoparticles as a delivery antigen/adjuvant carrier in the improvement of influenza immune responses.

Adherence to the DASH and Mediterranean diets is associated with decreased risk for gestational diabetes mellitus.

OBJECTIVES: Few studies have examined the association between adherence to the Dietary Approaches to Stop Hypertension (DASH) or Mediterranean (MED) diets and prevalence of gestational diabetes mellitus (GDM). The aim of the present study was to evaluate the association between the two diets and GDM. METHODS: In a case-control hospital-based study, pregnant women with (n = 200) and without (n = 260) GMD were recruited. An average of three 24-h dietary records were used to assess participants' dietary intakes. DASH scores were calculated based on the Fung method and MED scores were calculated using the Trichopoulou method. GDM was defined as fasting glucose >95 mg/dL or 1-h postprandial glucose >140 mg/dL for the first time in the pregnancy. The risk for GDM was assessed across tertiles of DASH and MED scores. RESULTS: DASH and MED diets were negatively related to fasting blood glucose, hemoglobin A1c, and serum triacylglycerol concentrations. High-density lipoprotein cholesterol was significantly higher for those in the top tertile of the DASH diet but not the MED diet in comparison with the lowest tertile. Total serum cholesterol level was lower in the third tertile of the MED diet but not in the DASH diet. Participants in the highest tertile of the MED diet had 80% lower risk for GDM compared with those in the lowest tertile (Ptrend = 0.006). Greater adherence to the DASH eating plan was associated with 71% reduced risk for GDM (Ptrend = 0.006) after adjustment for potential confounders. CONCLUSION: Adherence to either the DASH or Mediterranean diet is associated with decreased risk for GDM.

Effects of tamoxifen on the cervix and uterus in women with breast cancer: experience with Iranian patients and a literature review.

OBJECTIVE: Invasive breast cancer is the most common malignancy in women. Due to the declining mortality rate that is partly attributable to the use of screening mammography and effective adjuvant therapy, more women survive their breast cancers. The aim of this study was to evaluate the effects of tamoxifen on the genital tract with particular attention to the uterus and cervix. METHODS: We investigated the relationship between tamoxifen and cervical or uterine cancer in Iran, reviewing all the studies performed by the Vali-Asr Gynecology Oncology Clinic in Tehran. In addition, the available data on Medline from 1980 until 2009 were reviewed. RESULTS: A total of 182 articles showed associations with gynecologic malignancies. Although as many as 121 referred to links between the drug and endometrial abnormalities (polyps or cancers), 55 articles studied the relationship with changes of pap smears, four of which indicated isolated cervical metastasis followed tamoxifen use in patients with breast cancer. CONCLUSION: In spite of the significant relationship between tamoxifen and endometrial cancers, cervix is rarely involved in breast cancer patients. However, vaginal bleeding or abnormal vaginal discharge has been reported in all cases before the diagnosis was made. To rule out genital tract malignancy, it is necessary, therefore, to have an annual pelvic exam, pap smear and early endometrial with endocervical curettage for tamoxifen users following a breast cancer in those with abnormal uterine bleeding or persistent vaginal discharge.