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PubMed1995

Macular dystrophy associated with monogenic Arg172Trp mutation of the peripherin/RDS gene in a Japanese family.

OBJECTIVE: Mutations of the peripherin/RDS gene have been reported in several kinds of retinal dystrophy, and they show variation of manifestation. In some pedigrees, the same mutation can produce different phenotypic features, a factor that makes it difficult to deduce certain rules for genotype-phenotype correlations in the peripherin/RDS gene. The authors report the phenotypic features of a Japanese family with a mutation in codon 172 of the peripherin/RDS gene and compare them to previously reported ocular findings in British pedigrees with the same mutation. PATIENTS AND METHODS: A 45-year-old man and his 15-year-old son were screened for mutations in the peripherin/RDS gene and the ROM1 gene. Clinical features were characterized by visual acuity and visual field testing, fundus examination, fluorescein angiography, and electroretinography. RESULTS: Both patients had the same mutation in codon 172 of the peripherin/RDS gene designated as Arg172Trp. No mutation was found in the ROM1 gene in either patient. Clinical features were summarized as autosomal dominant macular dystrophy. The father had sharply demarcated chorioretinal atrophy in the macula. The son showed mild granularity in the macular area in ophthalmoscopic appearances. CONCLUSIONS: The Arg172Trp mutation was confirmed to produce autosomal dominant macular dystrophy. This particular phenotype was caused by the monogenic mutation in the peripherin/RDS gene.

Adolescent↗

PubMed2005

The genetic and molecular bases of monogenic disorders affecting proteolytic systems.

Complete and limited proteolysis represents key events that regulate many biological processes. At least 5% of the human genome codes for components of proteolytic processes if proteases, inhibitors, and cofactors are taken into account. Accordingly, disruption of proteolysis is involved in numerous pathological conditions. In particular, molecular genetic studies have identified a growing number of monogenic disorders caused by mutations in protease coding genes, highlighting the importance of this class of enzymes in development, organogenesis, immunity, and brain function. This review provides insights into the current knowledge about the molecular genetic causes of these disorders. It should be noted that most are due to loss of function mutations, indicating absolute requirement of proteolytic activities for normal cellular functions. Recent progress in understanding the function of the implicated proteins and the disease pathogenesis is detailed. In addition to providing important clues to the diagnosis, treatment, and pathophysiology of disease, functional characterisation of mutations in proteolytic systems emphasises the pleiotropic functions of proteases in the body homeostasis.

Animals↗

PubMed2006

Lentiviral-mediated fetal gene therapy for monogenic disorders: development of an in vitro rabbit model.

OBJECTIVE: Fetal gene replacement is a novel, potential therapy for monogenic disorders which are diagnosed prenatally. The purpose of this study was to develop in vitro, respiratory-epithelium targeted, lentiviral (LV)-mediated gene transfer in fetal rabbit tracheas. METHODS: Via triple plasmid transfection, vesicular stomatitis virus-G (VSV-G)-pseudotyped LV vector containing green fluorescent protein (GFP) marker gene, under the control of a cytomegalovirus promoter was constructed. LV bioavailability in rabbit amniotic fluid (AF) was evaluated by infectivity assays of 293T cell monolayers in variable concentrations of AF. Fetal tracheas from time-mated rabbits (term gestation, G = 31 days) were collected on G 23-25 days, and placed in tissue culture (substrate-enriched DMEM, 37 degrees C, 5% CO(2)/room air). The tracheal cultures were transfected with 1 x 10(5) LV particles, and analyzed daily for: reporter gene by polymerase chain reaction, and reporter gene product (GFP) by whole-mount fluoroscopy and immunohistochemistry. RESULTS: 293T cell infectivity assays confirmed bioavailability of LV in rabbit AF. Following in vitro transfection, GFP DNA and GFP were detectable in fetal rabbit tracheas by 4 and 5 days, respectively. Immunocytochemistry localized GFP to the luminal aspect of tracheal epithelium. CONCLUSIONS: In vitro, LV-mediated GFP gene transfer to fetal rabbit tracheas occurs within 4 days, and gene expression is evident by 5 days post-transfection. This observation, and the bioavailability of LV through AF, suggests the appropriateness of this model for the future evaluation of in vivo, transamniotic gene delivery strategies.

Amniotic Fluid↗

PubMed1983

Monogenic control of variations in antipyrine metabolite formation. New polymorphism of hepatic drug oxidation.

To investigate mechanisms that control large variations among normal uninduced subjects in the elimination of the model compound antipyrine (AP) and other drugs, AP was administered to 144 subjects (83 unrelated adults and 61 members of 13 families). Thereafter, at regular intervals for 72 h, the urine of each subject was collected and concentrations of AP and its three main metabolites measured. From these urinary concentrations, rate constants for formation of each AP metabolite were calculated. Trimodal curves were observed when values for each AP rate constant were plotted in 83 unrelated subjects; probit plots of these values showed inflections at the two antimodes of each trimodal distribution. All members of our 13 families were assigned one of three phenotypes determined by where their AP metabolite rate constant placed them in the trimodal distributions derived from the 83 unrelated subjects. In each family, pedigree analysis to identify the mode of transmission of these three phenotypes was consistent with their monogenic control. These results provide evidence for a new polymorphism of drug oxidation in man.

Adolescent↗

PubMed2005

The pattern of cognitive performance in CADASIL: a monogenic condition leading to subcortical ischemic vascular dementia.

OBJECTIVE: Subcortical ischemic vascular lesions, which are closely related to small vessel disease, are a common substrate of cognitive impairment and dementia. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic variant of small vessel disease resulting from mutations in NOTCH3. Mutation carriers almost invariably develop cognitive deficits and eventually dementia. The current study describes the profile of cognitive abnormalities in CADASIL subjects. METHOD: A cross-sectional study of 65 mutation carriers (mean age=47.3 years, SD=10.5) and 30 matched comparison subjects (mean age=47.2 years, SD=14.0) was conducted. Participants underwent a series of assessments that included ratings of global cognition, the cognitive portion of the Vascular Dementia Assessment Scale, and specific tests of executive function and attention with measures of processing speed and error monitoring. RESULTS: CADASIL subjects had pronounced impairments of the timed measures (Stroop II and III, Trail Making Test, symbol digit, digit cancellation). Measures of error monitoring (Stroop III, Trail Making Test, symbol digit, maze task) were also significantly affected but to a lesser extent. Prominent deficits further included verbal fluency and ideational praxis. Recall, orientation, and receptive language skills were largely preserved. Subgroup analyses indicated a similar profile in subjects with early and advanced impairment of global cognitive performance. CONCLUSIONS: The findings highlight processing speed as the most substantial area of cognitive impairment in CADASIL subjects, with less pronounced yet significant deficits in other aspects of executive performance and attention. This profile of cognitive impairment is present at an early stage and enables the construction of targeted test batteries for clinical trials. It is hypothesized that the profile of dysfunction described here represents the core of the cognitive syndrome associated with small vessel disease and subcortical ischemic vascular lesions.

Attention↗

PubMed2006

Semi-automated segmentation and quantification of adipose tissue in calf and thigh by MRI: a preliminary study in patients with monogenic metabolic syndrome.

BACKGROUND: With the growing prevalence of obesity and metabolic syndrome, reliable quantitative imaging methods for adipose tissue are required. Monogenic forms of the metabolic syndrome include Dunnigan-variety familial partial lipodystrophy subtypes 2 and 3 (FPLD2 and FPLD3), which are characterized by the loss of subcutaneous fat in the extremities. Through magnetic resonance imaging (MRI) of FPLD patients, we have developed a method of quantifying the core FPLD anthropometric phenotype, namely adipose tissue in the mid-calf and mid-thigh regions. METHODS: Four female subjects, including an FPLD2 subject (LMNA R482Q), an FPLD3 subject (PPARG F388L), and two control subjects were selected for MRI and analysis. MRI scans of subjects were performed on a 1.5T GE MR Medical system, with 17 transaxial slices comprising a 51 mm section obtained in both the mid-calf and mid-thigh regions. Using ImageJ 1.34 n software, analysis of raw MR images involved the creation of a connectedness map of the subcutaneous adipose tissue contours within the lower limb segment from a user-defined seed point. Quantification of the adipose tissue was then obtained after thresholding the connected map and counting the voxels (volumetric pixels) present within the specified region. RESULTS: MR images revealed significant differences in the amounts of subcutaneous adipose tissue in lower limb segments of FPLD3 and FPLD2 subjects: respectively, mid-calf, 15.5% and 0%, and mid-thigh, 25.0% and 13.3%. In comparison, old and young healthy controls had values, respectively, of mid-calf, 32.5% and 26.2%, and mid-thigh, 52.2% and 36.1%. The FPLD2 patient had significantly reduced subcutaneous adipose tissue compared to FPLD3 patient. CONCLUSION: Thus, semi-automated quantification of adipose tissue of the lower extremity can detect differences between individuals of various lipodystrophy genotypes and represents a potentially useful tool for extended quantitative phenotypic analysis of other genetic metabolic disorders.

Journal Article↗

PubMed1982

Testing the monogenic theory of schizophrenia: An application of segregation analysis to blind family study data.

Segregation analysis was applied to blind family data concerning schizophrenia to decide if the transmission of schizophrenia could be explained by a single major gene. Our results showed that the Mendelian model was unacceptable. Therefore, the monogenic hypothesis could not account for the transmission of schizophrenia. Since the hypothesis of no parent-child transmission was also not accepted, there was an indication that some form of vertical transmission existed which could be psychosocial, or an interaction between genetic and psychosocial factors. Our results suggest genetic heterogeneity in schizophrenia. Currently available clinical criteria for defining subgroups must be improved in conjunction with detection of biological indicators so that segregation analysis of family data could be effectively used in determining modes of transmission in schizophrenia.

Adult↗

PubMed2004

Monogenic human obesity syndromes.

Over the past decade, we have witnessed a major increase in the scale of scientific activity devoted to the study of energy balance and obesity. This explosion of interest has, to a large extent, been driven by the identification of genes responsible for murine obesity syndromes and the novel physiological pathways revealed by those genetic discoveries. We and others recently have identified several single-gene defects causing severe human obesity. Many of these defects have occurred in molecules identical or similar to those identified as a cause of obesity in rodents. This chapter will consider the human monogenic obesity syndromes that have been characterized to date and discuss how far such observations support the physiological role of these molecules in the regulation of human body weight and neuroendocrine function.

Energy Metabolism↗

PubMed1999

Disease taxonomy--monogenic muscular dystrophy.

The field of the autosomal recessive progressive muscular dystrophies has clarified significantly following the recent elucidation of the genetic and molecular etiology of a number of these entities. These studies illustrate how genetics provides a rationale and objective basis for a new, refined nosology. Furthermore, whereas most of these studies point towards the pivotal role played by a number of structural proteins--all directly or indirectly associated with dystrophin--a calpain protease was shown to be involved in the Réunion-type limb girdle muscular dystrophy. This discovery raises the issue of whether these mechanisms are all part of one and the same pathway or of distinct pathophysiological pathways (structuropathy versus enzymopathy) leading to similar phenotypes. Finally, all of these diseases are considered as classical monogenic traits. Some findings suggest, however, that epistatic interactions have been overlooked and that the inheritance models could be slightly more complex. These results are discussed in light of the coming challenges of the identification of genes underlying complex multifactorial traits.

Humans↗

PubMed2005

Adaptive monogenic filtering and normalization of ESPI fringe patterns.

A technique is presented for filtering and normalizing noisy fringe patterns, which may include closed fringes, so that single-frame demodulation schemes may be successfully applied. It is based on the construction of an adaptive filter as a linear combination of the responses of a set of isotropic bandpass filters. The space-varying coefficients are proportional to the envelope of the response of each filter, which in turn is computed by using the corresponding monogenic image [Felsberg and Sommer, IEEE Trans. Signal Process. 49, 3136 (2001)]. Some examples of demodulation of real Electronic Speckle Pattern Interferometry (ESPI) images patterns are presented.

Algorithms↗

PubMed2006

A look to future directions in gene therapy research for monogenic diseases.

The concept of gene therapy has long appealed to biomedical researchers and clinicians because it promised to treat certain diseases at their origins. In the last several years, there have been several trials in which patients have benefited from gene therapy protocols. This progress, however, has revealed important problems, including the problem of insertional oncogenesis. In this review, which focuses on monogenic diseases, we discuss the problem of insertional oncogenesis and identify areas for future research, such as developing more quantitative assays for risk and efficacy, and ways of minimizing the genotoxic effects of gene therapy protocols, which will be important if gene therapy is to fulfill its conceptual promise.

Animals↗

PubMed2006

Thiamine transporter mutation: an example of monogenic diabetes mellitus.

OBJECTIVE: Thiamine-responsive megaloblastic anemia (TRMA) is a rare syndrome characterized by diabetes mellitus (DM), anemia, and sensorineural deafness. We describe the clinical course and the molecular defect of a young woman who was diagnosed to have this syndrome. CASE: The patient is an 18-year-old girl who was born to non-consanguous parents. She was noted to be deaf-mute in the first year of life. She was diagnosed with DM at the age of 9 months and with severe anemia at the age of 2 years. An extensive work up could not identify the cause. She was treated with blood transfusions every 3-4 weeks for the past 16 years. A diagnosis of TRMA was suspected and the patient was treated with thiamine hydrochloride. Hemoglobin and platelets increased to normal values after a few weeks of thiamine therapy. Diabetic control significantly improved but she had no noticeable changes in the deafness. METHODS: Peripheral blood DNA was extracted from the patient, her mother, aunt, and a healthy sister. Exons and exon-intron boundaries of the thiamine transporter gene SLC19A2 were PCR amplified and directly sequenced. RESULTS: A G515C homozygous mutation was identified in the SLC19A2 gene of the patient. This mutation changes Gly to Arg at codon 172 (G172R). The mother, an aunt, and a sister had a heterozygous G172R mutation. CONCLUSIONS: Mutations in thiamine transporter gene, SLC19A2, causes a rare form of monogenic diabetes, anemia, and sensorineural deafness. Thiamine induces a remarkable hematological response and improvement in the diabetic control but has no effect on deafness.

Adolescent↗

PubMed2001

Molecular diagnostics in monogenic and multifactorial forms of type 2 diabetes.

Type 2 diabetes represents a major and increasing contributor to morbidity and mortality worldwide. Of the world's population, 10% either have Type 2 diabetes, or will develop it during their lifetime. Realization that inherited factors play a leading role in determining individual susceptibility to this condition provides a framework for improved molecular understanding of disease pathogenesis through susceptibility gene discovery. In particular, identification and characterization of these susceptibility variants should lead to improved targeting of available preventative and therapeutic measures and increasingly 'personalized' therapy. This article surveys present knowledge about the genetic basis of Type 2 diabetes and discusses the current and future role of genetic diagnostics, with an emphasis on lessons learned from study of monogenic forms of the disease.

Diabetes Mellitus, Type 2↗

PubMed2003

Primary hypercholesterolemia: genetic causes and treatment of five monogenic disorders.

Coronary heart disease is a major cause of death in Europe and the USA. Insudation of atherogenic lipoproteins, including low-density lipoprotein (LDL), into the artery wall is integral to atherosclerosis. It is clear that numerous genetic loci contribute to increased plasma levels of LDL. However, five specific monogenic disorders, three of which have been reported recently, are known to increase LDL. These are familial hypercholesterolemia (LDL receptor gene: LDLR); familial ligand-defective apoB- 100 (apoB gene: APOB); autosomal recessive hypercholesterolemia (ARH gene); sitosterolemia (ABCG5 or ABCG8 genes) and cholesterol 7alpha-hydroxylase deficiency (CYP7A1 gene). This review relates the mechanisms underlying these five disorders with specific therapeutic interventions.

Anticholesteremic Agents↗

PubMed2001

Case populations must match the respective disease model: Genotype diversity causes linkage disequilibrium mapping failure in monogenic disorders.

Traditional linkage analysis in large families is the most promising approach for mapping disease genes of monogenic heritable disorders when the number of informative meioses is sufficient. With rare diseases, however, the low availability of informative pedigrees poses a significant limitation. As an adjunct to family linkage methods, association studies based on the investigation of individual haplotypes from a number of unrelated patients (i.e. linkage disequilibrium analysis) have recently been employed in mapping hereditary disease loci. However, such haplotype analysis is hampered by a number of effects that influence statistical evaluation, e.g. i) population history and size, ii) allele and haplotype frequencies in the respective population(s), iii) heterogeneous mutation and natural selection processes, and iv) small sample sizes of patient groups. The purpose of the present study was to determine the utility and limitations of haplotype-based genetic mapping in estimating the location of the NYX gene, which has recently been identified as the causative gene for a rare inherited retinal disorder known as the complete type of X-linked congenital stationary night blindness (CSNB1). For this purpose we recapitulated haplotypes and tested for linkage disequilibrium in 20 unrelated male CSNB1 patients from three European populations and 44 healthy individuals. All subjects were genotyped for 17 polymorphic microsatellite loci covering the Xp11.4 region with an average marker density of approximately 0.29 cM. We found that a precise model to describe mutations at loci that erroneously break up linkage is highly required, and that the case population must match the respective disease model.

Adolescent↗

PubMed1994

Molecular biology techniques in the diagnosis of monogenic diseases.

Monogenic diseases are defined by their patterns of inheritance: autosomal dominant, autosomal recessive, or X-linked. This article examines the molecular biology techniques available for their study and detection. These techniques comprise direct detection of mutations (including trinucleotide repeats) and linkage analysis. The usefulness of these techniques is compared to conventional biochemical tests for the diagnosis of various inherited diseases. The authors stress the need for caution in the interpretation of test results and the importance of genetic counseling.

Forecasting↗

PubMed2000

[Detection and diagnosis of hereditary monogenic neurologic diseases in Slovakia].

Authors present a clinical symptoms recapitulation of the most important monogenic hereditary neuromuscular diseases, their molecular-genetic causes and the possibilities of diagnostic on the level of DNA analysis. Low detectability of these pathologic states in Slovak republic is stressed and possible causes of this state are analyzed. (Ref. 10.)

Humans↗

PubMedDate not supplied

The phenotypic diversity of monogenic disease: lessons from the thalassemias.

Clearly, the thalassemias are associated with a remarkably diverse series of phenotypes. Much of this heterogeneity can be explained at the molecular level by variability of the primary mutation of the beta globin genes, and the effects of genetic variability at two other loci, that is the alpha and gamma gene loci. When all these factors are taken into consideration there still remains a considerable amount of phenotypic diversity that is not explainable in this way. It is becoming clear that there is potential for further diversity at unrelated loci that may modify the major complications of the disease. And there is yet another layer of potential genetic variability that reflects the way in which these diseases have come under intense selection by malaria over a relatively short period of time. Finally, there are many environmental and cultural factors that may modify a patient's reaction to the disease. It is apparent, therefore, that this group of monogenic diseases are highly diverse and that, although much of this heterogeneity can be ascribed to the action of one or two major modifying loci, phenotypic variability also reflects the action of even further genetic diversity stemming from the way this disease has spread and its evolutionary background. It is apparent, therefore, that when we start to dissect disease due to the action of multiple loci, together with a major environmental component, the situation will be infinitely more complex. Of course this should not stop us from attempting to isolate the major genes involved, but it is telling us that we should be very careful about making assumptions that we will be able accurately to predict phenotypes from genotypes; although we have made considerable progress toward this end for the thalassemias, even here we have to deal with a large number of genetic and environmental factors that may modify the primary action of mutations of the beta globin genes. It is issues of this kind that will set the limit on our current reductionist approach to the study of human disease and will make it all the more important that we develop a more holistic way of analyzing disease processes in the future.

Alleles↗