| 11065114 | Shared Copy Number Variation in Simultaneous Nephroblastoma and Neuroblastoma due to Fanconi Anemia. | Serra A, etal., Mol Syndromol. 2012 Sep;3(3):120-130. Epub 2012 Aug 23. | Concurrent emergence of nephroblastoma (Wilms Tumor; WT) and neuroblastoma (NB) is rare and mostly observed in patients with severe subtypes of Fanconi anemia (FA) with or without VACTER-L association (VL). We investigated the hypothesis that early consequences of genomic instability result in share d regions with copy number variation in different precursor cells that originate distinct embryonal tumors. We observed a newborn girl with FA and VL (aplasia of the thumbs, cloacal atresia (urogenital sinus), tethered cord at L3/L4, muscular ventricular septum defect, and horseshoe-kidney with a single ureter) who simultaneously acquired an epithelial-type WT in the left portion of the kidney and a poorly differentiated adrenal NB in infancy. A novel homozygous germline frameshift mutation in PALB2 (c.1676_c1677delAAinsG) leading to protein truncation (pGln526ArgfsX1) inherited from consanguineous parents formed the genetic basis of FA-N. Spontaneous and induced chromosomal instability was detected in the majority of cells analyzed from peripheral lymphocytes, bone marrow, and cultured fibroblasts. Bone marrow cells also showed complex chromosome rearrangements consistent with the myelodysplastic syndrome at 11 months of age. Array-comparative genomic hybridization analyses of both WT and NB showed shared gains or amplifications within the chromosomal regions 11p15.5 and 17q21.31-q25.3, including genes that are reportedly implicated in tumor development such as IGF2, H19, WT2, BIRC5, and HRAS. | 23112754 | 2012-04-01 |
| 598116372 | Elucidation of MRAS-mediated Noonan syndrome with cardiac hypertrophy. | Higgins EM, etal., JCI Insight. 2017 Mar 9;2(5):e91225. doi: 10.1172/jci.insight.91225. | Noonan syndrome (NS; MIM 163950) is an autosomal dominant disorder and a member of a family of developmental disorders termed "RASopathies," which are caused mainly by gain-of-function mutations in genes encoding RAS/MAPK signaling pathway proteins. Whole exome sequencing (WES) and trio-based genomi c triangulation of a 15-year-old female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents identified a de novo variant in MRAS-encoded RAS-related protein 3 as the cause of her disease. Mutation analysis using in silico mutation prediction tools and molecular dynamics simulations predicted the identified variant, p.Gly23Val-MRAS, to be damaging to normal protein function and adversely affect effector interaction regions and the GTP-binding site. Subsequent ectopic expression experiments revealed a 40-fold increase in MRAS activation for p.Gly23Val-MRAS compared with WT-MRAS. Additional biochemical assays demonstrated enhanced activation of both RAS/MAPK pathway signaling and downstream gene expression in cells expressing p.Gly23Val-MRAS. Mutational analysis of MRAS in a cohort of 109 unrelated patients with phenotype-positive/genotype-negative NS and cardiac hypertrophy yielded another patient with a sporadic de novo MRAS variant (p.Thr68Ile, c.203C>T). Herein, we describe the discovery of mutations in MRAS in patients with NS and cardiac hypertrophy, establishing MRAS as the newest NS with cardiac hypertrophy-susceptibility gene. | 28289718 | 2017-03-09 |
| 329901810 | Genetic and functional analyses of MRAS and HNF1A genes in diabetes and diabetic nephropathy. | Horová E, etal., Folia Biol (Praha). 2012;58(3):121-7. | Evidence has recently indicated that the MRAS and HNF1A genetic polymorphisms are associated with coronary artery disease. The MRAS and HNF1A genes are located on chromosomes 3q and 12q within the regions where associations with diabetes and diabetic nephropathy occur. We thus performed genetic and functional analyses of these two genes to evaluate their impacts on diabetes and diabetic nephropathy. MRAS and HNF1A genetic polymorphisms were genotyped in 1399 Czech subjects including non-diabetic controls (339), type 1 (243) and type 2 (817) diabetic patients with and without diabetic nephropathy using TaqMan allelic discrimination. Gene expression levels in the kidneys of diabetic Goto-Kakizaki and Wistar rats were detected with real-time RT-PCR. Despite no significance in genetic analysis of diabetic subjects, SNP rs2259816 in the HNF1A gene tended to associate with diabetic nephropathy in type 1 diabetic patients. The hnf1a gene expression was significantly decreased in kidney tissues of Goto-Kakizaki rats compared to Wistar and insulin-treated Goto-Kakizaki rats. There was neither significant association in the MRAS genetic polymorphism with diabetic nephropathy nor variation of mras gene expression in the kidneys of Goto-Kakizaki and Wistar rats. Data from the present study have not proved any significant association of the MRAS and HNF1A genetic polymorphisms with diabetes and diabetic nephropathy in a cohort of Czech population. However, the functional analysis and the trend in genetic analysis suggest that the HNF1A gene may have primary genetic impact on the development of diabetic nephropathy. | 22849862 | 2012-12-01 |
| 598115441 | Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers. | Suzuki H, etal., Am J Med Genet A. 2019 Aug;179(8):1628-1630. doi: 10.1002/ajmg.a.61261. Epub 2019 Jun 7. | Activation of the RAS pathway through either the activation of genes that accelerate the pathway or the suppression of genes that inhibit the pathway leads to a group of disorders collectively referred to as RASopathies. The key molecules of the RAS pathway are KRAS, HRAS, and NRAS. Mutations in the se three RAS homolog genes have been shown to be associated with RASopathies. Recently, two patients with a Noonan syndrome phenotype were shown to carry mutations in the yet another RASopathy gene, MRAS (muscle RAS oncogene homolog). Here, we report a patient with a severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant, which represents a recurrent substitution in RAS homologs in various cancers. The patient's dysmorphic features included relative macrocephaly, a down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge, and low-set ears with thick lobes; these facial features are strongly associated with RASopathy. We confirmed that the MRAS gene represents a causative gene for RASopathy. | 31173466 | 2019-08-01 |
| 11342069 | Urinary Retention, Incontinence, and Dysregulation of Muscarinic Receptors in Male Mice Lacking Mras. | Ehrhardt A, etal., PLoS One. 2015 Oct 30;10(10):e0141493. doi: 10.1371/journal.pone.0141493. eCollection 2015. | Here we show that male, but not female mice lacking expression of the GTPase M-Ras developed urinary retention with distention of the bladder that exacerbated with age but occurred in the absence of obvious anatomical outlet obstruction. There were changes in detrusor morphology in Mras -weight:700;'>Mras-/- males: Smooth muscle tissue, which exhibited a compact organization in WT mice, appeared disorganized and became increasingly 'layered' with age in Mras-/- males, but was not fibrotic. Bladder tissue near the apex of bladders of Mras-/- males exhibited hypercontractility in response to the cholinergic agonist carbachol in in vitro, while responses in Mras-/- females were normal. In addition, spontaneous phasic contractions of detrusors from Mras-/- males were increased, and Mras-/- males exhibited urinary incontinence. We found that expression of the muscarinic M2 and M3 receptors that mediate the cholinergic contractile stimuli of the detrusor muscle was dysregulated in both Mras-/- males and females, although only males exhibited a urinary phenotype. Elevated expression of M2R in young males lacking M-Ras and failure to upregulate M3R with age resulted in significantly lower ratios of M3R/M2R expression that correlated with the bladder abnormalities. Our data suggests that M-Ras and M3R are functionally linked and that M-Ras is an important regulator of male bladder control in mice. Our observations also support the notion that bladder control is sexually dimorphic and is regulated through mechanisms that are largely independent of acetylcholine signaling in female mice. | 26516777 | 1000-07-01 |
