Genetic Abnormalities in a Calf with Congenital Increased Muscular Tonus.
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ABSTRACT:
SUBMITTER: Wiedemar N
PROVIDER: S-EPMC4858041 | biostudies-literature | 2015 Sep-Oct
REPOSITORIES: biostudies-literature
Publications
Genetic Abnormalities in a Calf with Congenital Increased Muscular Tonus.
Wiedemar N N Riedi A-K AK Jagannathan V V Drögemüller C C Meylan M M
Journal of veterinary internal medicine 20150820 5
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Project description:ObjectiveThe aim was to update the genetic and clinical advances of congenital muscular dystrophy (CMD), based on a systematic review of the literature from 1991 to 2017.Data sourcesArticles in English published in PubMed from 1991 to 2017 English were searched. The terms used in the literature searches were CMD.Study selectionThe task force initially identified citations for 98 published articles. Of the 98 articles, 52 studies were selected after further detailed review. Three articles, which were not written in English, were excluded from the study. This study referred to all the important and English literature in full.ResultsCMD is a group of early-onset disorders encompassing great clinical and genetic heterogeneity. Patients present with muscle weakness typically from birth to early infancy, delay or arrest of gross motor development, and joint and/or spinal rigidity. The diagnosis of CMD relies on clinical findings, brain and muscle imaging, muscle biopsy histology, muscle and/or skin immunohistochemical staining, and molecular genetic testing.ConclusionsAdvances in next-generation sequencing and histopathological techniques have enabled the recognition of distinct CMD subtypes supported by specific gene identification. Genetic counseling and multidisciplinary management of CMD play an important role in help patients and their family. Further elucidation of the significant clinical and genetic heterogeneity, therapeutic targets, and the clinical care for patients remains our challenge for the future.
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Project description:ObjectiveUllrich congenital muscular dystrophy (UCMD) corresponds to the severe end of the clinical spectrum of neuromuscular disorders caused by mutations in the genes encoding collagen VI (COL VI). We studied four unrelated families with six affected children that had typical UCMD with dominant and recessive inheritance.Materials & methodsFour unrelated Iranian families with six affected children with typical UCMD were analyzed for COLVI secretion in skin fibroblast culture and the secretion of COLVI in skin fibroblast culture using quantitative RT-PCR (Q-RT-PCR), and mutation identification was performed by sequencing of complementary DNA.ResultsCOL VI secretion was altered in all studied fibroblast cultures. Two affected sibs carried a homozygous nonsense mutation in exon 12 of COL6A2, while another patient had a large heterozygous deletion in exon 5-8 of COL6A2. The two other affected sibs had homozygote mutation in exon 24 of COL6A2, and the last one was homozygote in COL6A1.ConclusionIn this study, we found out variability in clinical findings and genetic inheritance among UCMD patients, so that the patient with complete absence of COLVI was severely affected and had a large heterozygous deletion in COL6A2. In contrast, the patients with homozygous deletion had mild to moderate decrease in the secretion of COL VI and were mildly to moderately affected.
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Project description:Large and giant congenital melanocytic nevi (CMN) are rare melanocytic lesions mostly caused by post-zygotic acquisition of NRAS alteration. However, large/giant CMN may exhibit phenotypic differences among distinct areas patients and in addition, patients differ in features such as presence of multiple CMN or Spilus-like lesions. Overall, 50 fresh-frozen biopsies corresponding to 37 phenotypically characterized areas of large/giant CMNs, 9 satellite lesions, 1 acquired nevus and 3 healthy skin biopsies were analyzed by a multigene panel and RNA sequencing (RNA-seq). Mutational screening showed mutations in 76.2% of large/giant CMN. NRAS mutation was found in 57.1% of cases, and mutations in other genes such as BRAF, KRAS, APC and MET were detected in 14.3% of patients. RNA-seq revealed the fusion transcript ZEB2-ALK and SOX5-RAF1 in large/giant CMN from two patients without point mutations. Both alterations were not detected in unaffected skin and were detected in different affected skin. These findings suggest that large/giant CMN may result from distinct molecular events in addition to NRAS mutations including point mutations and fusions transcripts.
2019-10-24 | GSE120597 | GEO
Project description:Congenital muscular dystrophy is a heterogeneous group of inherited muscle diseases characterized clinically by muscle weakness and hypotonia in early infancy. A number of genes harboring causative mutations have been identified, but several cases of congenital muscular dystrophy remain molecularly unresolved. We examined 15 individuals with a congenital muscular dystrophy characterized by early-onset muscle wasting, mental retardation, and peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center on muscle biopsy, and we have identified homozygous or compound heterozygous mutations in the gene encoding choline kinase beta (CHKB). This is the first enzymatic step in a biosynthetic pathway for phosphatidylcholine, the most abundant phospholipid in eukaryotes. In muscle of three affected individuals with nonsense mutations, choline kinase activities were undetectable, and phosphatidylcholine levels were decreased. We identified the human disease caused by disruption of a phospholipid de novo biosynthetic pathway, demonstrating the pivotal role of phosphatidylcholine in muscle and brain.
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Project description:The etiology for the majority of congenital heart defects (CHD) is unknown. We identified a patient with unbalanced atrioventricular septal defect (AVSD) and hypoplastic left ventricle who harbored an ~0.3 Mb monoallelic deletion on chromosome 3p14.1. The deletion encompassed the first four exons of FOXP1, a gene critical for normal heart development that represses cardiomyocyte proliferation and expression of Nkx2.5. To determine whether FOXP1 mutations are found in patients with CHD, we sequenced FOXP1 in 82 patients with AVSD or hypoplastic left heart syndrome. We discovered two patients who harbored a heterozygous c.1702C>T variant in FOXP1 that predicted a potentially deleterious substitution of a highly conserved proline (p.Pro568Ser). This variant was not found in 287 controls but is present in dbSNP at a 0.2% frequency. The orthologous murine Foxp1 p.Pro596Ser mutant protein displayed deficits in luciferase reporter assays and resulted in increased proliferation and Nkx2.5 expression in cardiomyoblasts. Our data suggest that haploinsufficiency of FOXP1 is associated with human CHD.
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Project description:Targeted deletion of focal adhesion kinase (fak) in the developing dorsal forebrain resulted in local disruptions of the cortical basement membrane located between the neuroepithelium and pia-meninges. At disruption sites, clusters of neurons invaded the marginal zone. Retraction of radial glial endfeet, midline fusion of brain hemispheres, and gliosis also occurred, similar to type II cobblestone lissencephaly as seen in congenital muscular dystrophy. Interestingly, targeted deletion of fak in neurons alone did not result in cortical ectopias, indicating that fak deletion from glia is required for neuronal mislocalization. Unexpectedly, fak deletion specifically from meningeal fibroblasts elicited similar cortical ectopias in vivo and altered laminin organization in vitro. These observations provide compelling evidence that FAK plays a key signaling role in cortical basement membrane assembly and/or remodeling. In addition, FAK is required within neurons during development because neuron-specific fak deletion alters dendritic morphology in the absence of lamination defects.
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Project description:A-type lamins, the intermediate filament proteins participating in nuclear structure and function, are encoded by LMNA. LMNA mutations can lead to laminopathies such as lipodystrophies, premature aging syndromes (progeria) and muscular dystrophies. Here, we identified a novel heterozygous LMNA p.R388P de novo mutation in a patient with a non-previously described severe phenotype comprising congenital muscular dystrophy (L-CMD) and lipodystrophy. In culture, the patient's skin fibroblasts entered prematurely into senescence, and some nuclei showed a lamina honeycomb pattern. C2C12 myoblasts were transfected with a construct carrying the patient's mutation; R388P-lamin A (LA) predominantly accumulated within the nucleoplasm and was depleted at the nuclear periphery, altering the anchorage of the inner nuclear membrane protein emerin and the nucleoplasmic protein LAP2-alpha. The mutant LA triggered a frequent and severe nuclear dysmorphy that occurred independently of prelamin A processing, as well as increased histone H3K9 acetylation. Nuclear dysmorphy was not significantly improved when transfected cells were treated with drugs disrupting microtubules or actin filaments or modifying the global histone acetylation pattern. Therefore, releasing any force exerted at the nuclear envelope by the cytoskeleton or chromatin did not rescue nuclear shape, in contrast to what was previously shown in Hutchinson-Gilford progeria due to other LMNA mutations. Our results point to the specific cytotoxic effect of the R388P-lamin A mutant, which is clinically related to a rare and severe multisystemic laminopathy phenotype.
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Project description:Fetal aberrant right subclavian artery (ARSA) is a relatively common sonographic finding. Congenital heart disease (CHD) is the most common structural abnormality in patients with ARSA. We aimed to assess the prevalence of genetic abnormalities, particularly sequence variants, in fetuses with CHD and ARSA. By clinical phenotyping and genomic sequencing, we retrospectively reviewed all fetuses with a prenatal diagnosis of CHD combined with ARSA at a single center. As a result, we identified 30 fetuses with ARSA combined with CHD, with conotruncal anomalies being the most common (n = 12, 40%), followed by left ventricular outflow tract obstruction (n = 6, 20%) and atrioventricular septal defects (n = 6, 20%). Overall, 18 (60%) cases had a genetic diagnosis. Copy number variation sequencing analysis identified six (20%) fetuses with aneuploidy and seven (23%) with pathogenic copy-number variants. Whole-exome sequencing (WES) analysis of the remaining 17 cases revealed diagnostic genetic variants in five (29%) cases, indicating that the diagnostic yield of WES for the entire cohort was 17% (5/30). Our findings reveal the high burden of genetic abnormalities in fetal CHD with ARSA. Single-gene disorders contribute substantially to the genetic etiology of fetal CHD with ARSA.
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Project description:Congenital heart disease (CHD) remains the most common birth defect in infants, and critical CHD is associated with significant rates of morbidity and mortality. With the advent of powerful yet noninvasive advanced fetal imaging, it is becoming increasingly evident that the presence of CHD in utero disrupts typical development and contributes to the lifelong morbidity in this population. Across healthy and high-risk populations, intrauterine influences can permanently alter fetal development that may manifest in complex morbidities later in life, the so-called fetal-onset-of-adult-disease (FOAD) phenomenon. The placenta plays a critical role in not only supporting fetal development, but also by adapting to specific intrauterine conditions. The role of placental health, adaptation and dysfunction, however, in CHD is not well understood. In this article, we will review current evidence relating placental health in CHD, appraise existing knowledge-gaps in the field and highlight promising new avenues to better understand the impact of placental function on fetal well-being. We will review evidence of ex vivo human placental studies that describe abnormal placental findings in pregnancies complicated by CHD, as well evidence for in vivo assessments of the human placenta. While overall clinical in vivo assessments of placental development are rather limited, we will also review emerging evidence from advanced quantitative and functional magnetic resonance imaging that are bringing new insights into placental structure and function throughout gestation. By providing novel information about placental development, we can now explore the maternal-fetal-placental connection in greater detail, and better understand the multi-factorial mechanisms that may contribute to adverse outcomes seen in survivors of CHD.
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Project description: Not available
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