Arthrogryposis, defined as congenital joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been ...described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases.
We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families.
Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic γ nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme-like 1 (ECEL1, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 FBN3, myosin IXA MYO9A, and pleckstrin and Sec7 domain containing 3 PSD3) were identified in 3 families (6.2%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis-associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type MYBPC2 and vacuolar protein sorting 8 VPS8, 2 families, 4.2%) or in another disease-associated genes (6 families, 12.5%), indicating a potential mutational burden contributing to disease expression.
In 58.3% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically heterogeneous disorders, such as arthrogryposis.
This work was supported in part by US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 to J.R. Lupski.
We evaluated the gene expression profiles of human dental pulp cells exposed to iRoot BP using microarray after 24 and 72 h. The results were verified using quantitative reverse transcriptase PCR ...analysis. Of the 36,000 transcripts arrayed, 21 were up-regulated and 15 were down-regulated by more than two fold. The largest group of up-regulated genes included those involved in nucleobase-containing compound metabolic processes, cell communication, protein metabolic processes, developmental processes, and biological regulation. The largest groups of down-regulated genes were those involved in cell communication, development, and biological regulation processes. In conclusion, iRoot BP affects the expression of genes involved in different biological processes in human dental pulp cells. (J Oral Sci 58, 307-315, 2016)
The primary purpose of this study was to examine the effects of triethylene glycol dimethacrylate (TEGDMA) on odontoclastic differentiation in the dental pulp tissue.
The effects of different TEGDMA ...dosages on the odontoclastic differentiation capability of dental pulp cells were analyzed in vitro using the following methodologies: i) flow cytometry and tartrate-resistant acid phosphatase (TRAP) staining; ii) apoptotic effects using Annexin V staining; iii) mRNA expression of osteoprotegerin (OPG) and receptor activator of nuclear factor (NF)-kB ligand (RANKL) genes by quantitative Real-time PCR (qRT-PCR); and iv) OPG and RANKL protein expression by enzyme-linked immunosorbent assay (ELISA).
TEGDMA caused relatively less odontoclastic differentiation in comparison with the control group; however, odontoclastic differentiation augmented with increasing doses of TEGDMA (p<0.05). The mRNA and protein expression of OPG was lower in TEGDMA treated pulp cells than in the control group (p<0.05). While the mRNA expression of RANKL remained unchanged compared to the control group (p>0.05), its protein expression was higher than the control group (p<0.05). In addition, TEGDMA increased the apoptosis of dental pulp cells dose dependently.
TEGDMA reduced the odontoclastic differentiation ability of human dental pulp cells. However, odontoclastic differentiation ratios increased proportionally with the increasing dose of TEGDMA.
Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, ...cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype-phenotype correlation studies.
Patients with Klinefelter Syndrome (KS) have increased cardiometabolic risk however the pathogenesis is not clear. We investigated the presence of endothelial dysfunction, insulin resistance and ...inflammation in an unconfounded population of KS.
A total of 32 patients with KS (mean age 21.59 ± 1.66 years) and 33 healthy control subjects (mean age: 22.15 ± 1.03 years) were enrolled. The demographic parameters, Asymmetric dimethylarginine (ADMA), homeostatic model assessment of insulin resistance (HOMA-IR) index and highsensitivity C-reactive protein (hs-CRP) levels were measured.
The patients had higher Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), insulin, HOMA-IR and ADMA levels (p < 0.001 for all) and lower High Density Lipoprotein Cholesterol (HDL-C) and total testosterone levels (p=0.002 and p<0.001, respectively), compared to the healthy controls. Total testosterone levels were significantly negatively correlated to ADMA (r = - 0.479, p < 0,001), hs-CRP (r = -0.291, p = 0.034) and positively correlated to HDL-C (r = 0.429, p = 0.001) levels. The multivariate analysis has shown that total testosterone (β = -0.412, p = 0.001) and TG (β = 0.332, p = 0.009) levels were the significant independent determinants of the plasma ADMA levels.
The results of the present study show that endothelial dysfunction and insulin resistance are prevalent even in the very young subjects with KS, who have no metabolic or cardiac problems at present. Also, hypogonadism seems to play an important role for increased cardiometabolic risk in patients with KS.
POU3F3 proteins are eukaryotic transcription factors and contribute to the processes in the development of brain and kidney. Pathogenic POU3F3 variants cause a neurodevelopmental disorder called ...Snijders Blok‐Fisher syndrome (SNIBFIS). This article reports a new SNIBFIS case harboring a novel heterozygous c.1018_1019delCAinsTT (p.Gln340Leu) variant in the POU3F3 gene. This variant affects the α2 helix of POU‐S domain and is predicted to be “pathogenic” by multiple in‐silico tools. The proband had severe intellectual disability, hypotonia, autistic features, sleep disturbances, and dysmorphic features. The association with epilepsy and hemangioma like two of the three previously reported patients with mutations in the POU‐S domain was also a remarkable finding to understand the importance of POU‐S domain. This clinical report also highlights the interest of reinterpretation of molecular data and brings a new perspective to the genotype–phenotype relationship in “Snijders Blok‐Fisher syndrome”.
We aimed to investigate the rate of
MEFV
, the gene mutated in familial Mediterranean fever, mutations in patients with myeloid neoplasm and to determine if known mutations of
MEFV
cause a tendency ...for myeloid neoplasms. The frequency of the five most common
MEFV
gene mutations (M694V, M680I, V726A, E148Q and M694I) was determined in 26 patients with myeloid neoplasm. We identified 1 homozygous (E148Q/E148Q), 1 compound heterozygous (M694V/E148Q) and 5 heterozygous
MEFV
gene mutations; none had their own and/or family history compatible with familial Mediterranean fever. The mean overall mutation rate was 0.269. We found a high frequency of carriers in patients with myelodysplastic syndrome (66.6%), polycythemia vera (33.3%) and acute myeloid leukemia (28.6%). However, there was no
MEFV
gene mutation in patients with chronic myeloid leukemia. In conclusion, this study reports for the first time a possibly high prevalence of
MEFV
gene mutations in patients with myeloid neoplasm, especially myelodysplastic syndrome, polycythemia vera and acute myeloid leukemia. Our findings could open new perspectives for
MEFV
gene mutations in myeloid neoplasms and its association with tumor promotion. Further research is needed to determine the actual role of
MEFV
gene mutations in these malignancies.
Correction to: Journal of Human Genetics (2015) 60, 1–9; doi:10.1038/jhg.2014.85; published online 9 October 2014 Since the advance online publication of this article, the authors of the above paper ...have noticed errors in the list of authors and affiliations. Article with correct authors informationnow appears in this issue.
Chronic arthritis of familial Mediterranean fever (FMF) involves weight-bearing joints and can occur in patients without a history of acute attack. Our aim was to investigate a possible causal ...relationship between FMF and osteoarthritis in a population in which FMF is quite common.
Patients with late stage primary osteoarthritis were enrolled, and five MEFV gene mutations were investigated. The frequency of MEFV gene mutations was compared among patients with osteoarthritis and a previous healthy group from our center.
One hundred patients with primary osteoarthritis and 100 healthy controls were studied. The frequency of MEFV gene mutations was significantly lower in the osteoarthritis group (9% vs. 19%). M694V was the most frequent mutation (5%) in the osteoarthritis group, whereas in the control group, E148Q was the most common (16%). In subgroup analyses, the mutation frequency of patients with hip osteoarthritis was not different from that of patients with knee osteoarthritis and controls (7.1%, 9.7%, and 19%, respectively). There were no differences among the three groups with respect to MEFV gene mutations other than E148Q (8.1% vs. 3.6%). E148Q was significantly lower in the osteoarthritis group than in the controls (16% vs. 1%), although the mutations did not differ between patients with knee osteoarthritis and controls.
In a population with a high prevalence of MEFV gene mutations, we did not find an increased mutation rate in patients with primary osteoarthritis. Furthermore, we found that some mutations were significantly less frequent in patients with osteoarthritis. Although the number of patients studied was insufficient to claim that E148Q gene mutation protects against osteoarthritis, the potential of this gene merits further investigation.
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