scholarly journals Molecular genetics and phenotypic features of congenital isolated hypogonadotropic hypogonadism

2021 ◽  
Vol 67 (4) ◽  
pp. 46-56
Author(s):  
K. D. Kokoreva ◽  
I. S. Chugunov ◽  
O. B. Bezlepkina
Keyword(s):  
Significant Contribution ◽  
Hypogonadotropic Hypogonadism ◽  
Molecular Genetic ◽  
Genetic Defect ◽  
Clinical Signs ◽  
Phenotype Correlation ◽  
Molecular Defects ◽  
Therapy Effectiveness ◽  
Phenotypic Features ◽  
And Function

Congenital isolated hypogonadotropic hypogonadism includes a group of diseases related to the defects of secretion and action of gonadotropin-releasing hormone (GNRH) and gonadotropins. In a half of cases congenital hypogonadism is associated with an impaired sense of smell. It’s named Kallmann syndrome. Now 40 genes are known to be associated with function of hypothalamus pituitary gland and gonads. Phenotypic features of hypogonadism and therapy effectiveness are related to different molecular defects. However clinical signs may vary even within the same family with the same molecular genetic defect. Genotype phenotype correlation in patients with congenital malformations prioritizes the search for mutations in candidate genes. There are data of significant contribution of oligogenicity into the phenotype of the disease are presented in the review. Moreover, an issue of current isolated hypogonadotropic hypogonadism definition and classification revision is raised in the review due to hypogonadotropic hypogonadism development while there are mutations in genes not associated with GNRH neurons secretion and function.

Abnormal Processing of the Glycoprotein IIb Transcript due to a Nonsense Mutation in Exon 17 Associated with Glanzmann’s Thrombasthenia

1995 ◽  
Vol 73 (05) ◽  
pp. 756-762 ◽  
Author(s):  
Yoshiaki Tomiyama ◽  
Hirokazu Kashiwagi ◽  
Satoru Kosugi ◽  
Masamichi Shiraga ◽  
Yoshio Kanayama ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Molecular Genetic ◽  
Genetic Defect ◽  
Nucleotide Sequence Analysis ◽  
Type I ◽  
Normal Amount ◽  
Immunoblot Assay ◽  
Glanzmann’S Thrombasthenia ◽  
Glanzmann's Thrombasthenia ◽  
Pcr Products

SummaryWe analyzed the molecular genetic defect responsible for type I Glanzmann’s thrombasthenia in a Japanese patient. In an immunoblot assay using polyclonal anti-GPIIb-IIIa antibodies, some GPIIIa (15% of normal amount) could be detected in the patient’s platelets, whereas GPIIb could not (<2% of normal amount). Nucleotide sequence analysis of platelet GPIIb mRNA-derived polymerase chain reaction (PCR) products revealed that patient’s GPIIb cDNA had a 75-bp deletion in the 3’ boundary of exon 17 resulting in an in-frame deletion of 25 amino acids. DNA analysis and family study revealed that the patient was a compound heterozygote of two GPIIb gene defects. One allele derived from her father was not expressed in platelets, and the other allele derived from her mother had a 9644C → T mutation which was located at the position -3 of the splice donor junction of exon 17 and resulted in a termination codon (TGA). Moreover, quantitative analysis demonstrated that the amount of the abnormal GPIIb transcript in the patient’s platelets was markedly reduced. Thus, the C → T mutation resulting in the abnormal splicing of GPIIb transcript and the reduction in its amount is responsible for Glanzmann’s thrombasthenia.

scholarly journals L2HGDH Missense Variant in a Cat with L-2-Hydroxyglutaric Aciduria

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 682
Author(s):  
Matthias Christen ◽  
Nils Janzen ◽  
Anne Fraser ◽  
Adrian C. Sewell ◽  
Vidhya Jagannathan ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Genetic Defect ◽  
Clinical Signs ◽  
Missense Variant ◽  
Microcytic Anemia ◽  
Abnormal Behavior ◽  
Functional Candidate Gene ◽  
History Of ◽  
The Brain ◽  
Hydroxyglutaric Acid

A 7-month-old, spayed female, domestic longhair cat with L-2-hydroxyglutaric aciduria (L-2-HGA) was investigated. The aim of this study was to investigate the clinical signs, metabolic changes and underlying genetic defect. The owner of the cat reported a 4-month history of multiple paroxysmal seizure-like episodes, characterized by running around the house, often in circles, with abnormal behavior, bumping into obstacles, salivating and often urinating. The episodes were followed by a period of disorientation and inappetence. Neurological examination revealed an absent bilateral menace response. Routine blood work revealed mild microcytic anemia but biochemistry, ammonia, lactate and pre- and post-prandial bile acids were unremarkable. MRI of the brain identified multifocal, bilaterally symmetrical and T2-weighted hyperintensities within the prosencephalon, mesencephalon and metencephalon, primarily affecting the grey matter. Urinary organic acids identified highly increased levels of L-2-hydroxyglutaric acid. The cat was treated with the anticonvulsants levetiracetam and phenobarbitone and has been seizure-free for 16 months. We sequenced the genome of the affected cat and compared the data to 48 control genomes. L2HGDH, coding for L-2-hydroxyglutarate dehydrogenase, was investigated as the top functional candidate gene. This search revealed a single private protein-changing variant in the affected cat. The identified homozygous variant, XM_023255678.1:c.1301A>G, is predicted to result in an amino acid change in the L2HGDH protein, XP_023111446.1:p.His434Arg. The available clinical and biochemical data together with current knowledge about L2HGDH variants and their functional impact in humans and dogs allow us to classify the p.His434Arg variant as a causative variant for the observed neurological signs in this cat.

STUDY OF CLINICAL CASES OF MYOCHE’S MYOPATHY AND DIFFERENTIAL DIAGNOSIS WITH OTHER TYPES OF ADVERSE MYOPATHIES

2021 ◽  
Author(s):  
K. Sarazhyna ◽  
Y. Solodovnikova ◽  
A. Son
Keyword(s):  
Case Report ◽  
Genetic Testing ◽  
Skeletal Muscles ◽  
Molecular Genetic ◽  
Clinical Signs ◽  
Lower Limbs ◽  
Molecular Genetic Testing ◽  
Membrane Repair ◽  
Rare Type ◽  
A Cell

Markesbery-Griggs myopathy, Miyoshi type (MM) is a rare type of myopathy, a form muscular dystrophy with the main involvement of the lower girdle and distal parts of the legs. Due to complexity of genetic testing, the diagnosis is mainly made on the neurological examination of the patient, which adds value to this case report. The childhood or adolescence onset of the disease is characterized initially by the calf muscles` wasting, accompanied by the severe elevation of the serum creatine kinase, as well as a slowly progressive ascending course. The disease refers to dysferlinopathies with various mutations in the DYSF gene. The dysferlin protein is localized in the plasma membrane and in the T-tubule system of skeletal muscles. Physiologically, skeletal muscles are constantly exposed to micromembrane lesions. Depending on the severity, these damages are restored using various complexes. One of the main reparative complexes is the dysferlin-dependent mechanism. Mutations can lead to a defect in the membrane repair, causing the influx of Ca 2+ into the cell, which leads to a cell`s destruction. There are three genetically identifiable types of Miyoshi myopathy: MMD1, MMD2, MMD3. The main clinical signs of the disease are the muscle weakness and atrophy, with predominant involvement of the distal parts of the lower limbs, especially in the gastrocnemius and plantar muscles. The MM causes tip toe walking disturbances and difficulties in climbing the stairs. Progression of the disease and further atrophy leads to the wasting of the lower girdle muscles, mainly gluteal ones. Peculiarity of these myopathies is the absence of cardiomyopathy, due to the immunity of cardiomyocytes to a deficiency of the protein dysferelin. Diagnosis is made on the basis of muscle biopsy and molecular genetic testing. The gold standard is immunoblotting or immunohistochemistry. One of treatment methods is the use of improperly folded dysferlin (treatment with a proteasome inhibitor MG-132) in fibroblasts with restoration of membrane sealing. The aim of this case report is to present an example of a possible clinical diagnosis of MM in a young man, in the absence of opportunities for molecular genetic testing.

scholarly journals Validating clinical characteristic of primary failure of eruption (PFE) associated with PTH1R variants

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Cristina Grippaudo ◽  
Isabella D’Apolito ◽  
Concetta Cafiero ◽  
Agnese Re ◽  
Pietro Chiurazzi ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Mutational Analysis ◽  
Clinical Signs ◽  
Open Bite ◽  
Clinical Severity ◽  
Mixed Dentition ◽  
Phenotype Correlation ◽  
Posterior Teeth ◽  
Primary Failure Of Eruption ◽  
Genotype Phenotype Correlation

Abstract Background Primary failure of eruption (PFE) is a hereditary condition, and linkage with variants in the PTH1R gene has been demonstrated in many cases. The clinical severity and expression of PFE is variable, and the genotype–phenotype correlation remains elusive. Further, the similarity between some eruption disorders that are not associated with PTH1R alterations is striking. To better understand the genotype–phenotype correlation, we examined the relationship between the eruption phenotype and PTH1R genotype in 44 patients with suspected PFE and 27 unaffected relatives. Sanger sequencing was employed to analyze carefully selected PFE patients. Potential pathogenicity of variants was evaluated against multiple genetic databases for function prediction and frequency information. Results Mutational analysis of the PTH1R coding sequence revealed 14 different variants in 38 individuals (30 patients and 8 first-degree relatives), 9 exonic and 5 intronic. Their pathogenicity has been reported and compared with the number and severity of clinical signs. In 72.7% of patients with pathogenic variants, five clinical and radiographic criteria have been found: involvement of posterior teeth, involvement of the distal teeth to the most mesial affected, supracrestal presentation, altered vertical growth of the alveolar process and posterior open-bite. In cases with mixed dentition (3), the deciduous molars of the affected quadrant were infraoccluded. Discussion The probability of an affected patient having a PTH1R variant is greater when five specific clinical characteristics are present. The likelihood of an eruption defect in the absence of specific clinical characteristics is rarely associated with a PTH1R mutation. Conclusions We report here that systematic clinical and radiographic observation using a diagnostic rubric is highly valuable in confirming PFE and offers a reliable alternative for accurate diagnosis.

scholarly journals GENETIC ASPECTS OF PREGNANCY MISCARRIAGE

2019 ◽  
pp. 71-76
Author(s):  
K. M. Lisova ◽  
I. V. Kalinovska ◽  
O. M. Yuzko
Keyword(s):  
Pregnant Women ◽  
Molecular Genetic ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Control Group ◽  
Molecular Genetic Study ◽  
Immunological Parameters ◽  
Fetoplacental Complex ◽  
Maternal Genotype ◽  
A1166c Polymorphism

Pregnancy miscarriage is a consequence of many factors. The aim of the study was to analyze the effect of miscarriage gene on embryometric, ultrasound, hormonal, immunological parameters in pregnant women, and to evaluate its prognostic value. The main group includes 31 pregnant women who had clinical signs of miscarriage in current or previous pregnancy. The control group consists of 32 healthy pregnant women whose clinical-paraclinical parameters served as a control to compare the data of the pregnancy survey of the main surveillance group. A general clinical examination and a special obstetrical examination (complaints, anamnesis, general medical examination, obstetric examination), biochemical studies (determination of hormones of the fetoplacental complex in blood serum of pregnant women), ultrasound, immunological studies, histological studies of the placenta, molecular genetic study A1166C polymorphism of the AGTR1 gene were made. In the course of the research, the genetic determinism of miscarriage was discovered. The polymorphism of the A1166C of the AGTR1 gene was considered as a prognostic marker of miscarriage in early gestational term and preeclampsia in the second half of pregnancy. A reliable marker of abortion was the maternal genotype 1166AC for the genome AGTR1. The risk of occurrence of clinical manifestations of abortion increased five times. At simultaneous influence of all prognostic factors the risk of abortion increased 6,25 times. Detection of genetic markers of pregnancy miscarriage will allow early correction of this pathology and prevent perinatal loss.

scholarly journals Normal Thyroid Structure and Function in Rhophilin 2-Deficient Mice

2005 ◽  
Vol 25 (7) ◽  
pp. 2846-2852 ◽  
Author(s):  
Jens Behrends ◽  
Serge Clément ◽  
Bernard Pajak ◽  
Viviane Pohl ◽  
Carine Maenhaut ◽  
...  
Keyword(s):  
Rho Gtpase ◽  
Clinical Signs ◽  
Structure And Function ◽  
Secretory Process ◽  
Thyroid Cell ◽  
Thyroid Cells ◽  
Thyroid Cell Culture ◽  
And Function ◽  
Deficient Mice ◽  
Stimulation Of

ABSTRACT Rhophilin 2 is a Rho GTPase binding protein initially isolated by differential screening of a chronically thyrotropin (TSH)-stimulated dog thyroid cDNA library. In thyroid cell culture, expression of rhophilin 2 mRNA and protein is enhanced following TSH stimulation of the cyclic AMP (cAMP) transduction cascade. Yeast two-hybrid screening and coimmunoprecipitation have revealed that the GTP-bound form of RhoB and components of the cytoskeleton are protein partners of rhophilin 2. These results led us to suggest that rhophilin 2 could play an important role downstream of RhoB in the control of endocytosis during the thyroid secretory process which follows stimulation of the TSH/cAMP pathway. To validate this hypothesis, we generated rhophilin 2-deficient mice and analyzed their thyroid structure and function. Mice lacking rhophilin 2 develop normally, have normal life spans, and are fertile. They have no visible goiter and no obvious clinical signs of hyper- or hypothyroidism. The morphology of thyroid cells and follicles in these mice were normal, as were the different biological tests performed to investigate thyroid function. Our results indicate that rhophilin 2 does not play an essential role in thyroid physiology.

Abstract 395: A Synonymous Coding SNP Alters SCN5A Regulation by miR-24 and Associates With Non-Arrhythmic Death in Heart Failure

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Xiaoming Zhang ◽  
Jin-Young Yoon ◽  
Michael Morley ◽  
Patrick Breheny ◽  
Heather Bloom ◽  
...  
Keyword(s):  
Heart Failure ◽  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Clinical Signs ◽  
Heart Rhythm ◽  
Coding Sequence ◽  
Reduced Ejection Fraction ◽  
Arrhythmic Death ◽  
And Function ◽  
Myocardial Gene Expression

Mutations disrupting SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and SNPs linked to SCN5A splicing, localization and function associate with heart failure-related sudden cardiac death. However, the clinical relevance of SNPs that modulate SCN5A expression levels remains understudied. Recently, we generated a transcriptome-wide map of microRNA (miR) binding sites in human heart and evaluated their interface with polymorphisms. Among >500 common SNPs residing within miR target regions, we identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within SCN5A coding sequence. This SNP is known to reproducibly associate with heart rhythm measurements, but is not considered to be “causal”. Here, we show that miR-24 potently suppresses SCN5A and that rs1805126 modulates this regulation. In further exploring the clinical significance of this, we found that rs1805126 minor allele homozygosity associates with decreased cardiac SCN5A expression and increased mortality in heart failure patients. Unexpectedly, this risk was not linked with arrhythmic sudden cardiac death, but rather, with clinical signs of worsening heart failure (e.g. reduced ejection fraction) and myocardial gene expression changes related to bioenergetics, inflammation and extracellular remodeling. Together, these data attribute a molecular mechanism to this firmly-established GWAS SNP and highlight a novel and surprising link between common variations in SCN5A expression and non-arrhythmic death in heart failure.

Neurodegenerative disorders in older people

2020 ◽  
pp. 601-611
Author(s):  
John Hindle
Keyword(s):  
Risk Factors ◽  
Older People ◽  
Protective Factors ◽  
Genetic Susceptibility ◽  
Neurodegenerative Disorders ◽  
Neuronal Death ◽  
Clinical Signs ◽  
Symptomatic Treatment ◽  
Structure And Function ◽  
And Function

Neurodegenerative disorders are associated with a progressive loss of structure and function of neurones that leads to neuronal death. Their aetiology combines ageing, genetic susceptibility, and risk factors including environmental exposure, balanced against protective factors. They present with varying combinations of progressive cognitive, emotional, motor, autonomic and peripheral symptoms, and clinical signs. Neurodegenerative conditions are all likely to have a preclinical prodromal period, followed by slow initial decline during which there is clinical presentation, followed by a further steady decline and an eventual accelerated decline. The rate of progression of these disorders varies greatly, but they are all inevitably progressive, currently have no cure, and require symptomatic treatment.

scholarly journals The factor VIII complex: structure and function

Blood ◽  
1981 ◽  
Vol 58 (1) ◽  
pp. 1-13 ◽  
Author(s):  
LW Hoyer
Keyword(s):  
Factor Viii ◽  
Complex Structure ◽  
Related Protein ◽  
Molecular Defects ◽  
Normal Human ◽  
And Function ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Antihemophilic Factor ◽  
Immunologic Properties

Abstract Normal human plasma contains a complex of two proteins that are important in hemostasis and coagulation. The factor VIII procoagulant protein (antihemophilic factor) and the factor VIII-related protein (von Willebrand factor) are under separate genetic control, have distinct biochemical and immunologic properties, and have unique and essential physiologic functions. While the nature of their interaction and the details of the biochemical structures remain to be determined, the information now available permits a preliminary understanding of the molecular defects in hemophilia and von Willebrand's diseases.

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