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At least 1,189 records · Page 66Linked to original sources
PubMed2004

Properties of slow- and fast-twitch skeletal muscle from mice with an inherited capacity for hypoxic exercise.

Muscle fiber type, myosin heavy chain (MHC) isoform composition, capillary density (CD) and citrate synthase (CS) activity were investigated in predominantly slow-twitch (soleus or SOL) and fast-twitch (extensor digitorum longus or EDL) skeletal muscle from mice with inherited differences in hypoxic exercise tolerance. Striking differences in hypoxic exercise tolerance previously have been found in two inbred strains of mice, Balb/cByJ (C) and C57BL/6J (B6), and their F1 hybrid following exposure to hypobaric hypoxia. Mice from the three strains were exposed for 8 weeks to either normobaric normoxia or hypobaric hypoxia (1/2 atm). Hypoxia exposure led to a slightly higher 2b fiber composition and a lower fiber area of types 1 and 2a in SOL of all mice. In the EDL, muscle fiber and MHC isoform composition remained unaffected by chronic hypoxia. Chronic hypoxia did not significantly affect CD in either muscle from any of the three strains. There were relatively larger differences in CS activity among strains and treatment, and in SOL the highest CS activity was found in the F1 mice that had been acclimated to hypoxia. In general, however, neither differences among strains nor treatment in these properties of muscle vary in a way that clearly relates to inherited hypoxic exercise tolerance.

Anaerobiosis↗
PubMed2006

Twelve different enzyme assays on dried-blood filter paper samples for detection of patients with selected inherited lysosomal storage diseases.

BACKGROUND: Diagnoses of inherited lysosomal storage diseases are based on specific enzymatic assays performed on plasma, leukocytes, fibroblasts, and lately, dried-blood filter paper samples. We evaluated feasibility of detecting of patients with several inherited lysosomal storage diseases using dried-blood filter paper samples for appropriate enzyme assays. METHODS: Fluorometric methods were used to evaluate the activities of arylsulfatase B, alpha-N-acetylglucosaminidase, chitotriosidase, alpha and beta-galactosidases, beta-glucosidase, beta-glucuronidase, total hexosaminidases, hexosaminidase A, alpha-iduronidase, and iduronate-2-sulfatase. A radiometric method was used for sphyngomyelinase determination. Single 3.0-mm diameter disks containing dried-blood samples were incubated at 37 degrees C with appropriate dilution buffers and artificial substrates, and the fluorescence or radioactivity was measured. RESULTS: Our results showed a statistically significant difference of the enzyme activity between affected individuals and controls, in all the assays performed. In contrast, we have not obtained a complete differentiation between heterozygotes and controls with these assays. CONCLUSIONS: Enzyme assay on dried-blood filter paper is a suitable method to screen for several lysosomal storage diseases. Despite the low individual incidence of these pathologies, the incorporation of individual enzyme assays in neonatal screening programs could be justified to screen for diseases with relatively high local frequency and therapeutic measures available.

Fluorometry↗
PubMed2004

Inherited interstitial lung disease.

This article focuses on recent advances in the identification of genes and genetic polymorphisms that have been implicated in the development of human interstitial lung diseases. It focuses on the inherited mendelian diseases in which pulmonary fibrosis is part of the clinical phenotype and the genetics of familial idiopathic pulmonary fibrosis and other rare inherited interstitial lung diseases. The article also reviews the association studies that have been published to date regarding the genetics of sporadic idiopathic pulmonary fibrosis. The reader is directed to recent reviews on human genetic predisposition of sarcoidosis, environmental-related, drug-related, connective tissue related pulmonary fibrosis, and genetic predisposition of fibrosis in animal models.

Comorbidity↗
PubMed2005

The sperm mitochondria-specific translocator has a key role in maternal mitochondrial inheritance.

The mechanism of maternal mitochondrial inheritance in animals involves the selective elimination of sperm mitochondria by the elimination factor of the egg and the sperm mitochondria-specific factor. In vitro fertilization using sperm from isogenic mice incorporating heterospecific mitochondrial DNA (mtDNA) showed that the number of PCR positives of sperm mtDNA in two-cell embryos was significantly increased following sperm incubation with anti-tetratricopeptide repeat-containing protein involved in spermatogenesis (tpis) protein, anti-translocator of mitochondrial outer membrane (Tom) 22 and anti-Tom40 antibodies. The treatment of fertilized eggs with EGTA and other endonuclease inhibitors increased the sperm mtDNA levels. We conclude that the elimination factor, which is probably an endonuclease, is selectively received by the tpis protein of the sperm mitochondrial outer membrane within the egg. It is then transported into the sperm mitochondria by Tom22 and Tom40, where it destroys the sperm mtDNA, establishing the maternal inheritance of mtDNA.

Animals↗
PubMed2006

Mitochondrial complex I activity is significantly decreased in a patient with maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy associated with mitochondrial DNA C3310T mutation: a cybrid study.

Mitochondrial respiratory function in a patient with maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy associated with heteroplasmic mitochondrial DNA (mtDNA) C3310T mutation, which replaces the second amino acid of NADH dehydrogenase 1 (ND1) from a hydrophobic Proline to a hydrophilic Serine, was investigated. Mitochondrial respiratory function solely due to mtDNA C3310T mutation was investigated in cybrid system by the fusion of mtDNA-deleted (rho(0)) HeLa cells and exogenous mtDNA either from the proband or from controls. Total oxygen consumption of the proband cybrid cells was significantly decreased compared with those of controls (2.468+/-0.475 versus 2.871+/-0.484 micromol/h/10(7) cells, p=0.0392). Mitochondrial respiratory chain complex I activity of the proband cybrid cells was also significantly decreased compared with those of controls (0.191+/-0.080 versus 0.288+/-0.113 micromol/h/mg protein, p=0.0223). Furthermore, ATP content in the proband cybrid cells was also significantly decreased compared with those in controls (1.119+/-0.344 versus 1.419+/-0.378 pmol/10(5) cells, p=0.044). The present study indicates that mtDNA C3310T mutation may be a pathogenic mutation of maternally inherited type 2 diabetes mellitus and hypertrophic cardiomyopathy in the proband and the family.

Blotting, Southern↗
PubMed2004

Screening for monogenetic del(GJB6-D13S1830) and digenic del(GJB6-D13S1830)/GJB2 patterns of inheritance in deaf individuals from Eastern Austria.

Genetically caused congenital deafness is a common trait affecting 1 in 2000 newborn children and is predominantly inherited in an autosomal recessive fashion. Genes such as the gap junction protein beta 2 (GJB2) encoding for Connexin (Cx26) and GJB6 (Cx30) are known to cause sensorineural deafness. Autosomal recessive deafness has been linked both to the monogenetic occurrence of mutated GJB2 or the GJB6 deletion del(GJB6-D13S1830) and digenic GJB2/del(GJB6-D13S1830) inheritance. Monogenetic GJB2 alterations are responsible for 25.5% of deafness in the eastern Austrian population. An additional 9.8% are heterozygous carriers of a single GJB2 mutation which is not responsible for deafness alone. Del(GJB6-D13S1830) and GJB2/del(GJB6-D13S1830) mutations have been shown to be the second most frequent cause of deafness in different populations. To address the question of the relevance of mutations in GJB6 either as a monogenetic or a digenic GJB2/del(GJB6-D13S1830) cause of deafness in this population, 76 unrelated individuals (33 families and 43 sporadic cases) were screened using PCR strategies. Similar to studies in other hard of hearing populations with similar or lower carrier frequencies of single GJB2 mutations, the presence of del(GJB6-D13S1830) was not detected in any individual within the patient group. Data therefore exclude a digenetic association of del(GJB6-D13S1830) with heterozygous GJB2 mutations as a cause of deafness in a representative sample of the population from Eastern Austria.

Austria↗
PubMed2004

Iron homeostasis and inherited iron overload disorders: an overview.

Iron is an ubiquitous metal of vital importance to the normal physiologic processes of many organisms. Recent discoveries of mutations in genes that lead to inherited iron overload diseases have advanced the understanding of iron homeostasis in humans. This article provides an overview of the human iron cycle, regulation of iron homeostasis, how perturbations in this homeostasis lead to iron overload disease in adults and children, and strategies for diagnosis of inherited iron overload.

Antimicrobial Cationic Peptides↗
PubMed2006

Recurrent intracardiac thrombosis as an unusual manifestation of inherited thrombophilia.

Patients with inherited thrombophilia are at high risk for the development of venous thrombosis that manifests mainly as deep venous thrombosis of the legs and/or pulmonary embolism. We report spontaneous right-sided intracardiac thrombosis in a young man as an unusual manifestation of inherited thrombophilia. The diagnosis of thrombophilia was confirmed by demonstration of the prothrombin-G20210A-mutation in the homozygous state. A second spontaneous intracardiac thrombosis occurred 3 years after discontinuation of oral anticoagulant treatment. This indicates the high risk for recurrence in patients developing intracardiac thrombosis in the absence of an underlying cardiac disease and warrants long-term oral anticoagulant treatment.

Adult↗
PubMed2005

The role of inherited and acquired factors in the development of porphyria cutanea tarda in the Argentinean population.

BACKGROUND: Inherited and environmental factors are implicated in the expression of porphyria cutanea tarda (PCT); the contribution of each factor depends on the population. OBJECTIVE: To provide a review of PCT cases diagnosed in Argentina over 24 years and evaluate the role of different precipitating factors in its pathogenesis. Methods Plasma and urinary porphyrin levels and erythrocyte uroporphyrinogen decarboxylase (URO-D) activity were determined. Potential precipitating factors were identified in each patient. Additional tests for hepatitis C virus (HCV) and hemochromatosis gene mutations were carried out. RESULTS: Several factors (mainly alcohol abuse in men and estrogen ingestion in women), alone or combined were identified in our patients. Prevalence of HCV infection was 35.2%. Inherited URO-D deficiency occurs in 25.0% of cases. H63D was the most common hemochromatosis gene mutation. High incidence of PCT associated with HIV infection was found. CONCLUSIONS: PCT is multifactorial. Therefore, knowledge of all risk factors in each patient is important for the management of the disease.

Adolescent↗
PubMed2026

Examining the impact on quality-of-life of those living with inherited optic neuropathies: an updated systematic review.

BACKGROUND: Inherited optic neuropathies (IONs) cause progressive visual loss and substantially affect quality of life. This updated systematic review aims to synthesize and evaluate evidence on the patient experience of living with IONs, identify currently used assessment tools, and highlight areas for improvement in research and clinical care. METHODS: We systematically searched MEDLINE, EMBASE, PsycINFO, CINAHL, and Scopus for studies on (i) inherited optic neuropathies; (ii) quality of life or health status; (iii) patient-reported outcome measures; and/or (iv) qualitative research. Inclusion was restricted to peer-reviewed studies. Screening, data extraction, and risk of bias assessment were conducted using Covidence. RESULTS: From 1775 unique records, 5 studies met the inclusion criteria. They evaluated quality-of-life outcomes in patients with Leber hereditary optic neuropathy or autosomal-dominant optic neuropathy across 6 countries. Patient-reported outcome measures used included National Eye Institute Visual Functioning Questionnaire-39, National Eye Institute Visual Functioning Questionnaire-25, Short-Form 12 Health Survey, Beck Depression Inventory, and Pittsburgh Sleep Quality Index. Only one study used qualitative interviews to explore the emotional, social, and financial impacts on patients and families. DISCUSSION: This updated systematic review builds upon previous work to further characterize the impact of ION on patients living with these conditions and the tools currently used to assess them. We highlight the need for a multifaceted approach to ION management, combining medical treatment with comprehensive psychosocial support to work toward more patient-centred care and improved quality of life for those living with these challenging conditions.

Humans↗
PubMed2026

Molecular diagnostic yield and barriers in inherited retinal diseases: a retrospective cohort study.

OBJECTIVE: To evaluate the diagnostic yield of panel-based genetic testing for inherited retinal diseases (IRDs) and identify barriers to molecular resolution. DESIGN: Retrospective cohort. PARTICIPANTS: A total of 404 patients with clinically confirmed IRDs who were evaluated at the Adult Inherited Retinal Dystrophy Service, Ontario, Canada (October 2021-September 2024). METHODS: Patients underwent targeted massive parallel sequencing panel testing. Diagnostic yield was calculated, and unresolved cases were reviewed. Associations between yield, phenotype, ethnicity, and sex were assessed using χ² analysis. RESULTS: Of 685 referrals, 570 had confirmed IRDs. After we excluded 140 pending results and 26 patients who declined testing, 404 patients were analyzed. At referral, 94 patients (23.2%) had a previous molecular diagnosis, and 138 (34.0%) were diagnosed through clinic-initiated testing, giving an overall yield of 57.4%. Yield varied significantly by phenotype (χ², P = 1.4 × 10⁻⁶), from 94.4% in vitelliform macular dystrophies to 25.0% in vitreoretinopathies, with no sex association (P = 1.0). Disease-causing variants were identified in 83 IRD-associated genes, most frequently ABCA4, USH2A, and BEST1. Of 172 unresolved cases, 62 (36.0%) had negative panels, and 110 (63.9%) were inconclusive, including 30 with unphased pathogenic variants in recessive genes and 10 with high-suspicion variants of uncertain significance. Key barriers included limited family availability for phasing, restricted access to functional assays, and lack of public coverage for whole-exome or whole-genome sequencing. CONCLUSIONS: Massive parallel sequencing-based panel testing achieved a 57% diagnostic yield in this IRD population. Success was strongly phenotype-dependent with substantial heterogeneity. Whole-exome sequencing, whole-genome sequencing, family segregation, and functional genomics could improve diagnostic outcomes and management.

Humans↗
PubMed2005

Dermal elastic fibres in the inherited hypermobile disorders.

BACKGROUND: Elastic fibres in the inherited hypermobile disorders are probably abnormal on the inherited grounds. The abnormality may contribute for diagnosis and investigation of connective tissue biology. OBJECTIVE: The abnormality will be specific for every disorders and disclosed in the age-dependent change when exposure-dependent change was excluded. MATERIALS AND METHODS: Skin specimens from Ehlers-Danlos syndrome and hypermobile syndrome, Marfan syndrome, Osteogenesis imperfecta type I, homocysteinuria and normal controls are studied by routine electron microscopy. Age-dependent ultrastructural change of broad elastic fibres was evaluated in reticular dermis. RESULTS: Age-dependent change was categorized in infantile, adolescent, adult and senile pattern. Infantile pattern showed normal ultrastructure. Degeneration was first found in adolescent pattern by disarrayed microfibrils and degenerate matrix. Degeneration proceeded in adult pattern and ended in senile pattern. Typical abnormality developed in adult pattern. Ehlers-Danlos syndrome and hypermobile syndrome showed no specific abnormality but the degeneration began earlier and was severer than the control. Marfan syndrome showed defects of microfibrils and matrix surface. Moth-eaten figure was characteristic. Osteogenesis imperfecta showed abnormal matrix and revealed homogenous bulges of matrix. Homocysteinuria was specified by numerous microfibrils on the matrix surface in infantile pattern. CONCLUSION: Abnormality of elastic fibre was recognized in the reticular dermis of elbow. Ehlers-Danlos syndrome and hypermobile syndrome showed no specific abnormality but the degeneration was more intensive than the control. Abnormality of Marfan syndrome was degeneration of elastic microfibrils and matrix surface, Osteogenesis imperfecta was characterized by excess amount of matrix. Homocysteinuria revealed numerous microfibrils. Ultrastructural abnormality provided grounds for studies on histopathology and biology of elastic fibre.

Adolescent↗
PubMed2006

Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations.

OBJECTIVE: To investigate cases of severe congenital neutropenia (SCN) to ascertain SCN inheritance after determining that the same sperm donor was used by 4 different families to impregnate mothers. STUDY DESIGN: Because the donor sperm was not available, alternative methods were used to determine whether the sperm donor transmitted SCN. DNA isolated from leukocytes was used to sequence the ELA2 gene in the affected children and their mothers. ELA2 was amplified by polymerase chain reaction (PCR), and the product was sequenced. PCR was also performed with genomic DNA from the mothers and affected children using a set of 22 microsatellite PCR primers on chromosomes 14 and 19 to establish linkage to the paternal allele. RESULTS: None of the mothers had a mutation in ELA2, but all 5 affected children had the same mutation affecting the fourth exon at site S97L. Linkage mapping analysis confirmed that all affected children had the same paternal allele on chromosome 19, which contains ELA2. CONCLUSIONS: Our findings indicate that the father provided consistent haplotypes leading to the expression of SCN in all affected children, supporting an autosomal dominant inheritance in which ELA2 mutations occur.

Child↗
PubMed2005

Inherited pericentric inversion of chromosome 16 in chronic phase of chronic myeloid leukaemia.

The simultaneous occurrence of two specific acquired chromosomal abnormalities in chronic or acute leukaemias is rare. Inherited chromosomal abnormalities are also rare events in the general population. In chronic myeloid leukaemia (CML), characterised by the t(9;22)(q34;q11), the inv(16)(p13q22) has been described associated with the acceleration of disease or onset of blast crisis. We report on a patient with chronic phase of CML and both acquired t(9;22)(q34;q11) and inherited inv(16)(p13q22), who obtained a complete remission of the disease after bone marrow transplant. Therefore, it is worth to comment that an additional chromosomal abnormality in disease does not obligatory mean transformation of the disease to a more aggressive form, since chromosomal abnormalities are also seen in normal individuals.

Adult↗
PubMed2005

Biological evidence for inheritance of exceptional longevity.

Subjects with exceptional longevity have a lower incidence and/or significant delay in the onset of age-related disease, and their family members may inherit biological factors that modulate aging processes and disease susceptibility. In a case control study, we aim to determine phenotype and genotype of exceptional longevity in a genetically homogenous population (Ashkenazi Jews), and their offspring, while an age-matched control group of Ashkenazi Jews was used as control groups. We demonstrated that exceptional longevity and healthy aging in humans is an inherited phenotype across three generations. Moreover, we demonstrated that subjects with exceptional longevity and their offspring have significantly larger high-density lipoprotein (HDL) levels and particle sizes and low-density lipoprotein (LDL) levels that reflect on their health and cognitive function performance. This phenotype have led us to study candidate genes involved in lipoprotein metabolism, and to the implication of homozygosity for the 405 valine (V) allele of cholesteryl ester transfer protein (CETP). A markedly higher frequency of a functional CETP variant that led to increased particle sizes of HDL and LDL and thus a better health performance is the first example of a phenotype and an associated genotype in humans with exceptional longevity. Hopefully, this line of research will lead us to establish which genotype is necessary (although not necessary sufficient) for a prolonged disease-free aging.

Age Factors↗
PubMed2006

Molecular mechanism based on self-replicating protein conformation for the inheritance of acquired information in humans.

Recent evidence challenges the paradigmatic view of nucleic acids as the sole mediators of hereditary information. Here I present a molecular mechanism that can explain how acquired information in humans in a DNA independent mode becomes innate and heritable. The model is based on self-replicating protein conformations, a concept derived from prion and amyloid biology. Information is stored in specific beta-sheet protein conformations that can act as cytoplasmic molecular memories. The conformational information can be transmitted to next generations in a non-nucleic acid based inheritance system utilizing the self-perpetuating potential of such beta-rich protein aggregates. Chaperones play a crucial role in the model by regulating and balancing the process of folding and misfolding; they also assist in preventing the development of aggregation-based disease. The protein conformation-mediated information system could represent an evolutionary conserved primordial mechanism: while the main strategy has been to ensure rapid folding of polypeptides into the native, functional conformation, the disfolded, beta-rich amyloidogenic state has provided advantage by providing a cytoplasmic, protease-resistant self-perpetuating DNA-independent adaptive inheritance system. The model offers an explanation for the problematic question of the evolution of complex behavioural traits and has even impact in the context of mammalian cloning: the protein conformation-based information localized in the somatic cytoplasm is lost when transferring nuclei only into enucleated oocytes. The protein conformation-based model presented herein postulates that proteins may contain much more information than determined by the nucleotide-triplet controlled peptide sequence and that there exists cross-talk and information exchange between proteins.

Amyloid↗
PubMed2004

Genes causing inherited cancer as beacons to identify the mechanisms of chemoresistance.

Mechanisms of resistance to cancer chemotherapy are poorly understood. Molecular pathways involving genes associated with inherited cancer syndromes could represent mechanisms of chemoresistance. Microarray techniques can identify simultaneous alterations in the mRNA expression of multiple genes, but identification of the exact mechanism responsible for a particular phenotype, including resistance to a specific drug, remains problematic. Genes in which mutations cause inherited cancers play vital roles in apoptosis, growth arrest and/or DNA repair, and are inactivated by somatic mutations, deletions or hypermethylation in most cancer tissues. Similarities between carcinogenic injury and cell damage created by chemotherapeutics suggests that somatic inactivation of such genes is crucially important to drug sensitivity.

Antineoplastic Agents↗
PubMed2005

Erythermalgia: molecular basis for an inherited pain syndrome.

Inherited erythermalgia (also termed erythromelalgia) is characterized by severe pain in the limbs in response to mild thermal stimuli or exercise. Its molecular basis has, until recently, been enigmatic. Studies of families with autosomal dominant erythermalgia have now demonstrated mutations in sodium channel Na(v)1.7, which is selectively expressed within nociceptive dorsal root ganglion and sympathetic ganglion neurons. Shifts in activation and deactivation, and enhanced responses to small stimuli in mutant channels, decrease the threshold for single impulses and high-frequency trains of impulses in pain-sensing neurons. Erythermalgia, the first inherited painful neuropathy to be understood at a molecular level, is a model disease that could hold lessons for other painful conditions and for the development of rational, mechanism-based treatments for pain.

Amino Acid Sequence↗