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BMC Medical Genomics Jan 2021Mutations in lysyl-tRNA synthetase (KARS1), an enzyme that charges tRNA with the amino acid lysine in both the cytoplasm and mitochondria, have been associated thus far...
BACKGROUND
Mutations in lysyl-tRNA synthetase (KARS1), an enzyme that charges tRNA with the amino acid lysine in both the cytoplasm and mitochondria, have been associated thus far with autosomal recessive Charcot-Marie-Tooth type CMTRIB, hearing loss type DFNB89, and mitochondrial encephalohepatopathy (MEH) featuring neurodevelopmental disorders with microcephaly, white matter changes, and cardiac and hepatic failure in less than 30 patients.
CASE PRESENTATION
We report the clinical, biochemical and molecular findings of a 14-month-old girl with severe MEH compatible clinical features, profound sensorineural hearing loss, leopard spot retinopathy, pancytopenia, and advanced liver disease with portal hypertension leading to death at the age of 30 months.
CONCLUSIONS
Whole exome sequencing identified two rare variants in KARS1 gene. Our report expands the allelic and clinical features of tRNA synthase disorders. Moreover, with our report we confirm the usefulness of WES as first tier diagnostic method in infants with complex multisystem phenotypes.
Topics: Child, Preschool; Female; Humans; Infant; Lysine-tRNA Ligase; Phenotype; Exome Sequencing
PubMed: 33478492
DOI: 10.1186/s12920-020-00863-1 -
Molekuliarnaia Biologiia 2016Tyrosyl phosphorylation participates in various pathological and physiological processes, which are regulated by protein tyrosine kinases (PTKs) and protein tyrosine... (Review)
Review
Tyrosyl phosphorylation participates in various pathological and physiological processes, which are regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). The Src homology-2 domain containing phosphatase SHP2 (encoded by PTPN11) is an important phosphatase, which was found to be implicated in the regulation of genetic disease, development, metabolic, neurological, muscle, skeletal disease and cancer. Germline mutations in PTPN11 cause the Noonan Syndrome, LEOPARD syndrome and metachondromatosis. Somatic PTPN11 mutations occur in hematologic malignancies and in solid tumors. SHP2 is also an important component in oncogenic signaling pathways. It may play different roles in different stages and positions of human cancers. Whether SHP2 is an oncogene or cancer suppressor gene remains to be elucidated. Elucidation of the regulatory mechanisms of SHP2 in human disease will provide new insights into disease and new targets for therapy. Here, we summarized the structural basis and recent research progression on SHP2 in various human disease, including genetic and cancer diseases.
Topics: Humans; LEOPARD Syndrome; Mutation; Neoplasms; Noonan Syndrome; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Signal Transduction
PubMed: 27028808
DOI: 10.7868/S0026898416010110 -
Molecular Syndromology Oct 2012The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD (LS), neurofibromatosis type...
The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD (LS), neurofibromatosis type 1, Costello and cardio-facio-cutaneous syndromes. LEOPARD is an acronym, mnemonic for the major manifestations of this disorder, characterized by multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. Though it is not included in the acronym, hypertrophic cardiomyopathy is the most frequent cardiac anomaly observed, representing a potentially life-threatening problem in these patients. PTPN11, RAF1 and BRAF are the genes known to be associated with LS, identifying molecular genetic testing of the 3 gene mutations in about 95% of affected individuals. PTPN11 mutations are the most frequently found. Eleven different missense PTPN11 mutations (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Pro) have been reported so far in LS, 2 of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases. Here, we provide an overview of clinical aspects of this disorder, the molecular mechanisms underlying pathogenesis and major genotype-phenotype correlations.
PubMed: 23239957
DOI: 10.1159/000342251 -
International Journal of Fertility &... Apr 2014Female genital tuberculosis remains as a major cause of tubal obstruction leading to infertility, especially in developing countries. The global prevalence of genital... (Review)
Review
Female genital tuberculosis remains as a major cause of tubal obstruction leading to infertility, especially in developing countries. The global prevalence of genital tuberculosis has increased during the past two decades due to increasing acquired immunodeficiency syndrome. Genital tuberculosis (TB) is commonly asymptomatic and it is diagnosed during infertility investigations. Despite of recent advances in imaging tools such as computed tomography (CT) scan, magnetic resonance imaging (MRI) and ultrasongraphy, hysterosalpinography has been considered as the standard screening test for evaluation of tubal infertility and as a valuable tool for diagnosis of female genital tuberculosis. Tuberculosis gives rise to various appearances on hysterosalpingography (HSG) from non-specific changes to specific findings. The present pictorial review illustrates and describes specific and non-specific radiographic features of female genital tuberculosis in two parts. Part I presents specific findings of tuberculosis related to tubes such as "beaded tube", "golf club tube", "pipestem tube", "cobble stone tube" and the "leopard skin tube". Part II will describe adverse effects of tuberculosis on structure of endometrium and radiological specific findings, such as "T-shaped" tuberculosis uterus, "pseudo-unicornuate "uterus, "collar-stud abscess" and "dwarfed" uterus with lymphatic intravasation and occluded tubes which have not been encountered in the majority of non-tuberculosis cases.
PubMed: 24696765
DOI: No ID Found -
Case Reports in Genetics 2021LEOPARD syndrome is a rare congenital anomaly that involves several organs. Patients with this syndrome develop multiple lentigines resembling a leopard's hide. LEOPARD...
LEOPARD syndrome is a rare congenital anomaly that involves several organs. Patients with this syndrome develop multiple lentigines resembling a leopard's hide. LEOPARD is an acronym of the major features constituting the syndrome including lentigines, electrocardiographic conduction defects, ocular hypertelorism, pulmonary valve stenosis, anomalies of genitalia, retardation of growth, and deafness. The syndrome is rare, and only 200 cases have been reported yet worldwide. We present the case of an 8-year-old female patient who visited the Ho Chi Minh City Hospital of Dermato-Venereology because of multiple brownish-black "dots" on her face and body. On examination, she also showed abnormalities in the maxillofacial bones, vertebrae, shoulders, sternum, and teeth, as well as deaf-mutism and growth retardation, which are typical of LEOPARD syndrome. Genetic analysis revealed a gene mutation in this case. To the best of our knowledge, this is the first case of LEOPARD syndrome reported in Vietnam.
PubMed: 34552798
DOI: 10.1155/2021/8197435 -
Molecular and Cellular Biology Aug 2014Noonan syndrome (NS) is an autosomal dominant disorder caused by activating mutations in the PTPN11 gene encoding Shp2, which manifests in congenital heart disease,...
Noonan syndrome (NS) is an autosomal dominant disorder caused by activating mutations in the PTPN11 gene encoding Shp2, which manifests in congenital heart disease, short stature, and facial dysmorphia. The complexity of Shp2 signaling is exemplified by the observation that LEOPARD syndrome (LS) patients possess inactivating PTPN11 mutations yet exhibit similar symptoms to NS. Here, we identify "protein zero-related" (PZR), a transmembrane glycoprotein that interfaces with the extracellular matrix to promote cell migration, as a major hyper-tyrosyl-phosphorylated protein in mouse and zebrafish models of NS and LS. PZR hyper-tyrosyl phosphorylation is facilitated in a phosphatase-independent manner by enhanced Src recruitment to NS and LS Shp2. In zebrafish, PZR overexpression recapitulated NS and LS phenotypes. PZR was required for zebrafish gastrulation in a manner dependent upon PZR tyrosyl phosphorylation. Hence, we identify PZR as an NS and LS target. Enhanced PZR-mediated membrane recruitment of Shp2 serves as a common mechanism to direct overlapping pathophysiological characteristics of these PTPN11 mutations.
Topics: Animals; Female; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins; LEOPARD Syndrome; Male; Mice; Mice, Inbred C57BL; Mutation; NIH 3T3 Cells; Noonan Syndrome; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Signal Transduction; Zebrafish
PubMed: 24865967
DOI: 10.1128/MCB.00135-14 -
The Journal of Biological Chemistry Apr 2013SHP2 is an allosteric phosphatase essential for growth factor-mediated Ras activation. Germ-line mutations in SHP2 cause clinically similar LEOPARD and Noonan syndromes,...
SHP2 is an allosteric phosphatase essential for growth factor-mediated Ras activation. Germ-line mutations in SHP2 cause clinically similar LEOPARD and Noonan syndromes, two of several autosomal-dominant conditions characterized by gain-of-function mutations in the Ras pathway. Interestingly, Noonan syndrome SHP2 mutants are constitutively active, whereas LEOPARD syndrome SHP2 mutants exhibit reduced phosphatase activity. How do catalytically impaired LEOPARD syndrome mutants engender gain-of-function phenotypes? Our study reveals that LEOPARD syndrome mutations weaken the intramolecular interaction between the N-SH2 and phosphatase domains, leading to a change in SHP2 molecular switching mechanism. Consequently, LEOPARD syndrome SHP2 mutants bind upstream activators preferentially and are hypersensitive to growth factor stimulation. They also stay longer with scaffolding adapters, thus prolonging substrate turnover, which compensates for the reduced phosphatase activity. The study provides a solid framework for understanding how individual SHP2 mutations cause diseases.
Topics: Crystallography, X-Ray; Humans; LEOPARD Syndrome; Mutation; Protein Structure, Tertiary; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Structure-Activity Relationship
PubMed: 23457302
DOI: 10.1074/jbc.M113.450023 -
Differentiation; Research in Biological... Jul 2012This review discusses the function of neural crest as they relate to cardiovascular defects. The cardiac neural crest cells are a subpopulation of cranial neural crest... (Review)
Review
This review discusses the function of neural crest as they relate to cardiovascular defects. The cardiac neural crest cells are a subpopulation of cranial neural crest discovered nearly 30 years ago by ablation of premigratory neural crest. The cardiac neural crest cells are necessary for normal cardiovascular development. We begin with a description of the crest cells in normal development, including their function in remodeling the pharyngeal arch arteries, outflow tract septation, valvulogenesis, and development of the cardiac conduction system. The cells are also responsible for modulating signaling in the caudal pharynx, including the second heart field. Many of the molecular pathways that are known to influence specification, migration, patterning and final targeting of the cardiac neural crest cells are reviewed. The cardiac neural crest cells play a critical role in the pathogenesis of various human cardiocraniofacial syndromes such as DiGeorge, Velocardiofacial, CHARGE, Fetal Alcohol, Alagille, LEOPARD, and Noonan syndromes, as well as Retinoic Acid Embryopathy. The loss of neural crest cells or their dysfunction may not always directly cause abnormal cardiovascular development, but are involved secondarily because crest cells represent a major component in the complex tissue interactions in the head, pharynx and outflow tract. Thus many of the human syndromes linking defects in the heart, face and brain can be better understood when considered within the context of a single cardiocraniofacial developmental module with the neural crest being a key cell type that interconnects the regions.
Topics: Abnormalities, Multiple; Animals; Cell Differentiation; Cell Proliferation; Craniofacial Abnormalities; Disease Models, Animal; Heart; Heart Defects, Congenital; Humans; Metabolic Networks and Pathways; Mice; Myocytes, Cardiac; Neural Crest; Neurons; Syndrome
PubMed: 22595346
DOI: 10.1016/j.diff.2012.04.005 -
PloS One 2021The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) showed susceptibility to diverse animal species. We conducted this study to understand the spatial...
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) showed susceptibility to diverse animal species. We conducted this study to understand the spatial epidemiology, genetic diversity, and statistically significant genetic similarity along with per-gene recombination events of SARS-CoV-2 and related viruses (SC2r-CoVs) in animals globally. We collected a number of different animal species infected with SARS-CoV-2 and its related viruses. Then, we retrieved genome sequences of SARS-CoV-2 and SC2r-CoVs from GISAID and NCBI GenBank for genomic and mutational analysis. Although the evolutionary origin of SARS-CoV-2 remains elusive, the diverse SC2r-CoV have been detected in multiple Rhinolophus bat species and in Malayan pangolin. To date, human-to-animal spillover events have been reported in cat, dog, tiger, lion, gorilla, leopard, ferret, puma, cougar, otter, and mink in 25 countries. Phylogeny and genetic recombination events of SC2r-CoVs showed higher similarity to the bat coronavirus RaTG13 and BANAL-103 for most of the genes and to some Malayan pangolin coronavirus (CoV) strains for the N protein from bats and pangolin showed close resemblance to SARS-CoV-2. The clustering of animal and human strains from the same geographical area has proved human-to-animal transmission of the virus. The Alpha, Delta and Mu-variant of SARS-CoV-2 was detected in dog, gorilla, lion, tiger, otter, and cat in the USA, India, Czech Republic, Belgium, and France with momentous genetic similarity with human SARS-CoV-2 sequences. The mink variant mutation (spike_Y453F) was detected in both humans and domestic cats. Moreover, the dog was affected mostly by clade O (66.7%), whereas cat and American mink were affected by clade GR (31.6 and 49.7%, respectively). The α-variant was detected as 2.6% in cat, 4.8% in dog, 14.3% in tiger, 66.7% in gorilla, and 77.3% in lion. The highest mutations observed in mink where the substitution of D614G in spike (95.2%) and P323L in NSP12 (95.2%) protein. In dog, cat, gorilla, lion, and tiger, Y505H and Y453F were the common mutations followed by Y145del, Y144del, and V70I in S protein. We recommend vaccine provision for pet and zoo animals to reduce the chance of transmission in animals. Besides, continuous epidemiological and genomic surveillance of coronaviruses in animal host is crucial to find out the immediate ancestor of SARS-CoV-2 and to prevent future CoVs threats to humans.
Topics: COVID-19; Genetic Variation; Phylogeny; SARS-CoV-2
PubMed: 34910734
DOI: 10.1371/journal.pone.0260635 -
Anais Brasileiros de Dermatologia 2017Hypertrophic cardiomyopathy is known as Leopard syndrome, which is a mnemonic rule for multiple lentigines (L), electrocardiographic conduction abnormalities (E), ocular...
Hypertrophic cardiomyopathy is known as Leopard syndrome, which is a mnemonic rule for multiple lentigines (L), electrocardiographic conduction abnormalities (E), ocular hypertelorism (O), pulmonary stenosis (P), abnormalities of genitalia (A), retardation of growth (R), and deafness (D). We report the case of a 12-year-old patient with some of the abovementioned characteristics: hypertelorism, macroglossia, lentigines, hypospadias, cryptorchidism, subaortic stenosis, growth retardation, and hearing impairment. Due to this set of symptoms, we diagnosed Leopard syndrome.
Topics: Child; Humans; LEOPARD Syndrome; Male; Phenotype
PubMed: 28225973
DOI: 10.1590/abd1806-4841.20174505