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Project description:High throughput sequencing of atypical progeria caused by LMNA R527C mutation
| PRJNA786245 | ENA
Project description:Mandibuloacral dysplasia type A (MADA) is a rare autosomal recessive disorder, characterized by growth retardation, skeletal abnormality with progressive osteolysis of the distal phalanges and clavicles, craniofacial anomalies with mandibular hypoplasia, lipodystrophy and mottled cutaneous pigmentation. Some patients may show progeroid features. MADA with partial lipodystrophy, more marked acral, can be caused by homozygous or compound heterozygous mutation in the gene encoding lamin A and lamin C (LMNA). MADA and Hutchinson-Gilford progeria syndrome are caused by the same gene and may represent a single disorder with varying degrees of severity. MAD patients characterized by generalized lipodystrophy (type B) affecting the face as well as extremities and severe progressive glomerulopathy present heterozygous compound mutations in the ZMPSTE24 gene.We described a rare pedigree from Southern China, among them all three children presented with phenotypes of MADA associated progeria. The two elder sisters had developed severe mandibular hypoplasia associated progeria since the age of 1 year. The eldest sister showed a progressive osteolysis. The youngest son of 10 months showed severer lesions than those of his sisters at the same age, and presented possible muscle damage, and his symptoms progressed gradually. Three genes mutations including LMNA, ZMPSTE24 and BANF1 were tested in the family. LMNA gene sequencing revealed a homozygous missense mutation, c.1579C > T, p.R527C for all three siblings, and heterozygous mutations for their parents, whereas no mutations of ZMPSTE24 and BANF1 genes was detected among them.The same homozygous mutation of c.1579C > T of LMNA gene led to MADA associated progeria for the present family. The course of osteolysis for MADA is progressive.
| S-EPMC4287574 | biostudies-literature
Project description:Products of the LMNA gene, primarily lamin A and C, are key components of the nuclear lamina, a proteinaceous meshwork that underlies the inner nuclear membrane and is essential for proper nuclear architecture. Alterations in lamin A and C that disrupt the integrity of the nuclear lamina affect a whole repertoire of nuclear functions, causing cellular decline. In humans, hundreds of mutations in the LMNA gene have been identified and correlated with over a dozen degenerative disorders, referred to as laminopathies. These diseases include neuropathies, muscular dystrophies, lipodystrophies, and premature aging diseases. This review focuses on one of the most severe laminopathies, Hutchinson-Gilford Progeria Syndrome (HGPS), which is caused by aberrant splicing of the LMNA gene and expression of a mutant product called progerin. Here, we discuss current views about the molecular mechanisms that contribute to the pathophysiology of this devastating disease, as well as the strategies being tested in vitro and in vivo to counteract progerin toxicity. In particular, progerin accumulation elicits nuclear morphological abnormalities, misregulated gene expression, defects in DNA repair, telomere shortening, and genomic instability, all of which limit cellular proliferative capacity. In patients harboring this mutation, a severe premature aging disease develops during childhood. Interestingly, progerin is also produced in senescent cells and cells from old individuals, suggesting that progerin accumulation might be a factor in physiological aging. Deciphering the molecular mechanisms whereby progerin expression leads to HGPS is an emergent area of research, which could bring us closer to understanding the pathology of aging.
| S-EPMC5195863 | biostudies-literature
Project description:Hutchinson-Gilford progeria syndrome (HGPS) and Werner's syndrome are representative types of progeroid syndrome. LMNA (Lamin A/C) gene mutation with atypical Werner's syndrome have recently been reported. Atypical Werner's syndrome with the severe metabolic complications, the extent of the lipodystrophy is associated with A133L mutation in the LMNA gene and these patients present with phenotypically heterogeneous disorders. We experienced a 15-yr-old Korean female with progeroid features, generalized lipodystrophy, hypertriglyceridemia, fatty liver, steatohepatitis, and type 2 diabetes mellitus. Skin fibroblasts from the patient showed marked abnormal nuclear morphology, compared with that from normal persons. Gene analysis revealed that this patient had T506del of exon 2 in the LMNA gene. We report here the first case of atypical Werner's syndrome with frameshift mutation that was caused by T506del.
| S-EPMC2687649 | biostudies-literature
Project description:Forward genetic approaches have limited use for agronomic traits that can't be reliably scored on a single plant basis. Thus, mutants in wheat and other crops are more useful for gene function studies by reverse genetic approach. With a long-term goal to develop a sequence-based mutation detection resource in hexaploid wheat, we conducted a feasibility study to accurately differentiate induced mutations from the homoeologs' sequence variations present among the three wheat genomes.A reduced representation ApeKI library consisting of 21 Ethylmethane Sulfonate (EMS) induced mutants and two wild type cv. Indian plants was developed using individual barcode adapters and sequenced. A novel bioinformatics pipeline was developed to identify sequence variants using 178,464 wheat unigenes as a reference wheat transcriptome. In total, 14,130 mutational changes [Single Nucleotide Polymorphisms (SNPs) and Insertions/Deletions (INDELs)] and 150,511 homoeologous sequence changes were detected. On an average, 662 SNPs (ranging from 46 to 1,330) and 10 small INDELs (ranging from 0 to 23) were identified for each of the mutants. A mutation frequency of one per 5 Kb was observed with 70 % being transitions and 30 % transversions. The pipeline was tested using the known sequence changes in the three wheat genes. Genes present in the distal regions of the chromosomes were found to be more prone to EMS compared to genes present in the proximal regions. Redefined parameters identified a total of 28,348 mutational changes (1,349/plant).We conclude that sequencing based mutation detection is a valuable method to identify induced mutations at large.
| S-EPMC4650848 | biostudies-literature
Project description:Mandibuloacral dysplasia (MAD) is a rare autosomal recessive progeroid syndrome due to mutations in genes encoding nuclear lamina proteins, lamins A/C (LMNA) or prelamin A processing enzyme, and zinc metalloproteinase (ZMPSTE24).The aim of the study was to investigate the underlying genetic and molecular basis of the phenotype of a 7-yr-old girl with MAD belonging to a consanguineous pedigree and with severe progeroid features and lipodystrophy.The patient developed mandibular hypoplasia during infancy and joint stiffness, skin thinning, and mottled hyperpigmentation at 15 months. Progressive clavicular hypoplasia, acroosteolysis, and severe loss of hair from the temporal and occipital areas were noticed at 3 yr. At 5 yr, cranial sutures were still open and lipodystrophy of the limbs was prominent. GH therapy from the ages of 3-7 yr did not improve the short stature. Severe joint contractures resulted in abnormal posture and decreased mobility. We studied her skin fibroblasts for nuclear morphology and immunoblotting and determined the in vitro effects of various pharmacological interventions on fibroblasts.LMNA gene sequencing revealed a homozygous missense mutation, c.1579C>T, p.Arg527Cys. Immunoblotting of skin fibroblast lysate with lamin A/C antibody revealed no prelamin A accumulation. Immunofluorescence staining of the nuclei for lamin A/C in fibroblasts revealed marked nuclear morphological abnormalities. This abnormal phenotype could not be rescued with inhibitors of farnesyl transferase, geranylgeranyl transferase, or histone deacetylase.Severe progeroid features in MAD could result from LMNA mutation, which does not lead to accumulation of prenylated lamin A or prelamin A.
| S-EPMC2626450 | biostudies-other
Project description:Mandibuloacral dysplasia (MAD) is a rare disease resulting from a mutation of LMNA gene encoding lamins A and C. The most common mutation associated with this disease is a homozygous arginine 527 replacement by histidine. Three female patients originating from two unrelated families from Northeast Egypt were examined. Their growth was retarded; they had microcephaly, widened cranial sutures, prominent eyes and cheeks, micrognathia, dental crowding, hypoplastic mandible, acro-osteolysis of distal phalanges, and joint contractures. In addition, they presented some progeroid features, such as pinched nose, premature loss of teeth, loss of hair, scleroderma-like skin atrophy, spine rigidity, and waddling gait. The clinical presentation of the disease varied between the patient originating from Family 1 and patients from Family 2, suggesting that unknown, possibly epigenetic factors, modify the course of the disease. The first symptoms of the disease appeared at the age of 2.5 (a girl from Family 1), 5, and 3 years (girls from Family 2). All patients had the same, novel homozygous c.1580G>T LMNA mutation, resulting in the replacement of arginine 527 by leucine. Computational predictions of such substitution effects suggested that it might alter protein stability and increase the tendency for protein aggregation, and as a result, might influence its interaction with other proteins. In addition, restriction fragment-length polymorphism analysis performed in 178 unrelated individuals showed that up to 1.12% of inhabitants of Northeast Egypt might be heterozygous carriers of this mutation, suggesting the presence of a founder effect in this area.
| S-EPMC3476705 | biostudies-literature
Project description:Phenotype-driven approaches in mice are powerful strategies for the discovery of genes and gene functions and for unravelling complex biological mechanisms. Traditional methods for mutation discovery are reliable and robust, but they can also be laborious and time consuming. Recently, high-throughput sequencing (HTS) technologies have revolutionised the process of forward genetics in mice by paving the way to rapid mutation discovery. However, successful application of HTS for mutation discovery relies heavily on the sequencing approach employed and strategies for data analysis. Here we review current HTS applications and resources for mutation discovery and provide an overview of the practical considerations for HTS implementation and data analysis.
| S-EPMC3724459 | biostudies-literature
Project description:We investigated two siblings, born to consanguineous parents, with neurological features reminiscent of adaptor protein complex 4 (AP4) deficiency, an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity, severe intellectual disability speech delay, microcephaly, and growth retardation. Yet, both children also presented with early onset obesity. Whole-exome sequencing identified two homozygous substitutions in two genes 170 kb apart on 7q22.1: a c.1137+1G>T splice mutation in AP4M1 previously described in a familial case of AP4-deficiency syndrome and the AZGP1 c.595A>T missense variant. Haplotyping analysis indicated a founder effect of the AP4M1 mutation, whereas the AZGP1 mutation arose more recently in our family. AZGP1 encodes an adipokine that stimulate lipolysis in adipocytes and regulates body weight in mice. We propose that the siblings' phenotype results from the combined effects of mutations in both AP4M1 and AZGP1 that account for the neurological signs and the morbid obesity of early onset, respectively. Contiguous gene syndromes are the consequence of loss of two or more adjacent genes sensible to gene dosage and the phenotype reflects a combination of endophenotypes. We propose to broaden this concept to phenotypes resulting from independent mutations in two genetically linked genes causing a contiguous mutation syndrome.
| S-EPMC4444163 | biostudies-literature
Project description:Mandibuloacral dysplasia (MAD) is a rare autosomal recessive disorder, characterized by postnatal growth retardation, craniofacial anomalies, skeletal malformations, and mottled cutaneous pigmentation. The LMNA gene encoding two nuclear envelope proteins (lamins A and C [lamin A/C]) maps to chromosome 1q21 and has been associated with five distinct pathologies, including Dunnigan-type familial partial lipodystrophy, a condition that is characterized by subcutaneous fat loss and is invariably associated with insulin resistance and diabetes. Since patients with MAD frequently have partial lipodystrophy and insulin resistance, we hypothesized that the disease may be caused by mutations in the LMNA gene. We analyzed five consanguineous Italian families and demonstrated linkage of MAD to chromosome 1q21, by use of homozygosity mapping. We then sequenced the LMNA gene and identified a homozygous missense mutation (R527H) that was shared by all affected patients. Patient skin fibroblasts showed nuclei that presented abnormal lamin A/C distribution and a dysmorphic envelope, thus demonstrating the pathogenic effect of the R527H LMNA mutation.
| S-EPMC379176 | biostudies-literature