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PubMed1999

Monogenic diabetes mellitus in youth. The MODY syndromes.

Maturity onset diabetes of the young is characterized by early onset diabetes inherited in an autosomal dominant pattern. Classic MODY occurs predominantly in Caucasians and presents before age 25, is nonketotic, and is generally not insulin-requiring. Less than 5% of cases of childhood diabetes in Caucasians are caused by MODY. ADM is a subtype of MODY that occurs in approximately 10% of African-Americans with youth onset diabetes. In contrast to MODY in Caucasians, ADM presents clinically as acute onset diabetes often associated with weight loss, ketosis, and even diabetic ketoacidosis. Approximately 50% of patients with ADM are obese. Therefore, based strictly on clinical grounds, at onset, ADM cannot be distinguished from type 1 diabetes. Months to years following diagnosis, a non-insulin-dependent clinical course develops in patients with ADM that is clearly different from type 1 diabetes. Mutations in five genes can cause MODY. These genes encode hepatocyte nuclear factor-4 alpha (HNF-4 alpha, MODY1), glucokinase (MODY2), hepatocyte nuclear factor-1 alpha (HNF-1 alpha, MODY3), insulin promoter factor-1 (IPF-1, MODY4), and hepatocyte nuclear factor-1 beta (HNF-1 beta, MODY5). These monogenic forms of MODY have been used as model systems to investigate the inheritance and pathophysiology of type 2 diabetes. Clinicians, should be able to diagnose MODY. Type 1 diabetes, the most common form of diabetes in Caucasians, is always insulin-requiring for control and survival, whereas patients with MODY do not usually require long-term insulin for survival. Diagnostic confusion can lead to inappropriate management and patient expectations. Primary care physicians must be alert to avoid therapeutic confusion when patients with ADM enter into the non-insulin-dependent stage. An approach to the diagnosis of childhood diabetes is offered in Table 4. The majority of youth onset diabetes remains type 1; however, the frequency of type 2 diabetes is rising in obese children and adolescents and especially in obese minority youth. The diagnosis of MODY can be made through a careful review of the patient's clinical course, severity of hyperglycemia, and family history. The identification of islet autoantibodies is confirmatory evidence of autoimmune (type 1) diabetes. Because testing for MODY mutations is expensive and is performed at a select number of research laboratories only, routine molecular genetic studies to search for the various MODY mutations should be limited to research investigations. In the future, the availability of gene chip technology may allow rapid screening of mitochondrial and MODY mutations.

Adolescent↗
PubMed2004

Monogenic idiopathic epilepsies.

Major advances have recently been made in our understanding of the genetic bases of monogenic inherited epilepsies. Direct molecular diagnosis is now possible in numerous inherited symptomatic epilepsies. Progress has also been spectacular with respect to several idiopathic epilepsies that are caused by mutations in genes encoding subunits of ion channels or neurotransmitter receptors. Although these findings concern only a few families and sporadic cases, their potential importance is great, because these genes are implicated in a wide range of more common epileptic disorders and seizure types as well as some rare syndromes. Functional studies of these mutations, while leading to further progress in the neurobiology of the epilepsies, will help to refine genotype-phenotype relations and increase our understanding of responses to antiepileptic drugs. In this article, we review the clinical and genetic data on most of the idiopathic human epilepsies and epileptic contexts in which the association of epilepsy and febrile convulsions is genetically determined.

Animals↗
PubMed1997

Monogenic models of obesity.

The study of rodent monogenic models of obesity has yielded significant insights into the pathogenesis of obesity. Multiple independent mutations in several genes can produce obesity. As these genes act in different regulatory pathways, it is clear that multiple mechanisms can produce obesity. Furthermore, a single gene defect can produce regulatory deficits in multiple modes of energy expenditure. The most severe forms of genetic obesity involve multiple pathogenic processes. It is significant that regulatory defects in any single component of caloric intake or energy expenditure appear to be sufficient to produce obesity. Finally, the systems regulating energy balance are loosely coupled; positive and negative influences are not completely balanced, both in strength as well as temporally.

Animals↗
PubMed2001

Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias.

The remarkable phenotypic diversity of the beta-thalassaemias reflects the heterogeneity of mutations at the beta-globin locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors. It is likely that phenotype-genotype relationships will be equally complex in the case of many monogenic diseases. These findings highlight the problems that might be encountered in defining the relationship between the genome and the environment in multifactorial disorders, in which the degree of heritability might be relatively low and several environmental agents are involved. They also emphasize the value of an understanding of phenotype-genotype relationships in designing approaches to gene therapy.

Alleles↗
PubMed2026

The importance of integrating genetic testing into reproductive medicine: a retrospective observational study investigating the monogenic causes of human infertility in couples considering ICSI.

The genetic landscape of human infertility is complex with diverse etiologies. Identifying the underlying etiology is crucial for guiding reproductive decisions and improving management for infertile couples. Here, we aim to report on the molecular spectrum of monogenic genetic causes of reproductive failure. Over a 3-year period, we recruited all infertile couples considering assisted reproductive technologies (ART) for whom the underlying genetic cause had been identified, in either partner, using exome sequencing (ES). Clinical data of all participants along with their hormonal profiles, sonographic findings and spermograms were recorded. The study included 50 couples with primary infertility. Clinically, male factor infertility was documented in 26 patients, female factor infertility in 10, while reproductive failure was unexplained in the remaining 14 couples. All participating couples had potentially disease-causing variants in infertility genes. ES identified variants related to male infertility in 26 men, while variants in female infertility-related genes were detected in the remaining couples (n = 24). According to ACMG classification criteria, 78% (39/50) of couples harbored pathogenic/likely pathogenic (P/LP) variants, whereas 22% (11/50) carried variants of uncertain significance (VUS). In view of the identified genetic etiologies, the cohort was stratified into two groups based on the predicted reproductive outcome: (1) couples with significantly impaired reproductive potential, and (2) couples who can have biological children using appropriate medical interventions. However, classifications involving VUS were interpreted cautiously and considered exploratory. This study provides further evidence for the molecular heterogeneity of human infertility and highlights the usefulness of genetic testing for infertile couples pursuing ARTs.

Humans↗
PubMed2004

Monogenic X-linked mental retardation: is it as frequent as currently estimated? The paradox of the ARX (Aristaless X) mutations.

Mental retardation affects 30 to 50% more males than females, and X-linked mental retardation (XLMR) is thought to account for the major part of this sex bias. Nonsyndromic XLMR is very heterogeneous, with more than 15 genes identified to date, each of them accounting for a very small proportion of nonsyndromic families. The Aristaless X (ARX) gene is an exception since it was found mutated in 11 of 136 such families, with a highly recurrent mutation (dup24) leading to an expansion of a polyalanine tract in the protein. The rather high frequency of dup24 reported in families with clear X-linked MR (6.6%) contrasts with the very low prevalence of this mutation observed in sporadic male MR (0.13%). We conclude that monogenic XLMR has much lower prevalence in male MR (< 10%) than the 23% that would be required to account for a 30% male excess of mental retardation.

Chromosomes, Human, X↗
PubMed2002

Application of SFHR to gene therapy of monogenic disorders.

Gene therapy treatment of disease will be greatly facilitated by the identification of genetic mutations through the Human Genome Project. The specific treatment will ultimately depend on the type of mutation as different genetic lesions will require different gene therapies. For example, large rearrangements and translocations may call for complementation with vectors containing the cDNA for the wild-type (wt) gene. On the other hand, smaller lesions, such as the reversion, addition or deletion of only a few base pairs, on single genes, or monogenic disorders, lend themselves to gene targeting. The potential for one gene targeting technique, small fragment homologous replacement (SFHR) to the gene therapy treatment of sickle cell disease (SCD) is presented. Successful conversion of the wt-beta-globin locus to a SCD genotype of human lymphocytes (K562) and progenitor/stem hematopoietic cells (CD34(+) and lin-CD38-) was achieved by electroporation or microinjection small DNA fragments (SDF).

Antigens, CD34↗
PubMed2001

Autonomic nervous system function in patients with monogenic hypertension and brachydactyly: a field study in north-eastern Turkey.

Laboratory studies in patients with autosomal-dominant hypertension and brachydactyly showed increased sensitivity to sympathetic stimuli and severe abnormalities in baroreflex buffering. To further elucidate the mechanisms by which impaired baroreflex sensitivity could influence blood pressure (BP), we conducted autonomic testing under field conditions. We studied 17 hypertensive affected (13 to 48 years, BMI 22.7 +/- 6.5 kg/m(2), 160 +/- 23/98 +/- 15 mm Hg) and 12 normotensive non-affected (9 to 60 years, BMI 24.0 +/- 4.7 kg/m(2), 120 +/- 16/70 +/- 10 mm Hg) family members. Pulse intervals and finger BP were measured using the Portapres device. Valsalva ratio, the blood pressure overshoot during phase IV of the Valsalva manoeuver, the Ewing coefficient (RR30/15 ratio), and heart rate and BP variability were similar in affected and non-affected family members. Overall, baroreflex sensitivity calculated using the cross-spectral (BRSLF, BRSHF) and sequence techniques (BRS+, BRS-) was not different between the groups. However, in younger family members, BRS+ was 12 +/- 3.7 and 22 +/- 13 msec/mm Hg in affected and in non-affected family members, respectively. The decline in BRS with age and with increasing blood pressure was absent in affected family members. We conclude that autonomic reflex testing conducted under field conditions is not impaired in patients with monogenic hypertension and brachydactyly. However, noninvasive testing showed impaired baroreflex control of heart rate at a young age. The reduced BRS in young family members with moderate arterial hypertension may suggest that the impaired baroreflex function is not secondary to the hypertension but rather a primary abnormality, which aggravates the progression of hypertension.

Adolescent↗
PubMed2000

Monogenic inheritance of apomixis in two Hieracium species with distinct developmental mechanisms.

Apomixis, the asexual formation of seed, has been known in angiosperms for more than a century yet the genetic mechanisms that control this trait remain poorly understood. Most members of the genus Hieracium are apomicts, forming predominantly asexual seed. Some purely sexual forms, however, also exist. In this paper we present a study of the inheritance of apomixis using two apomictic species of Hieracium which utilize very different forms of megagametogenesis. In both cases the progeny inherited apomixis as a monogenic, dominant trait that could be transferred by both haploid and diploid male gametes. In common with observations from other systems, no diploid apomictic progeny were recovered from these crosses. This appears to have been caused by selection against the survival of diploid zygotes, rather than against the mediation of haploid gametes as has been noted in other systems. Crosses between the two apomicts showed that the dominant determinants in the two forms examined were closely linked, possibly allelic. The significance of these data is discussed with respect to current theories on the associative link between gametophytic apomixis and polyploidy.

Alleles↗
PubMed1997

Use of Arabidopsis recombinant inbred lines reveals a monogenic and a novel digenic resistance mechanism to Xanthomonas campestris pv campestris.

Infiltration of the Arabidopsis thaliana accession Landsberg erecta (Ler) with Xanthomonas campestris pv campestris isolate 2D520 results in extensive necrosis and limited chlorosis within 5-6 days post-inoculation (d.p.i.), which can lead to systemic necrosis within 23 d.p.i. in contrast, the accession Columbia (Col) remains asymptomatic after infiltration. Although both accessions support bacterial growth, 5-28-fold more bacteria are present in Ler than in Col leaf tissue. Inheritance studies indicate that three independent, dominant or partially dominant, nuclear genes condition resistance to X. c. campestris 2D520. The major gene, termed RXC2, conditions monogenic resistance to X. c.; campestris and was mapped to a 5.5 cM interval of chromosome V. Segregation data indicate that the locus RXC3 in conjunction with RXC4 confers digenic resistance to X. c. campestris. The combined action of RXC3 and RXC4 is correlated with a suppression of in planta bacterial levels and a suppression of symptoms relative to Ler. The RXC3 + RXC4-mediated resistance is novel in that although the Col allele of RXC4 contributes positively to resistance, it is the Ler and not the Col allele of RXC3 that contributes positively to resistance. RXC3 was mapped to the bottom arm of chromosome V in a 2.7 cM interval within the major recognition gene complex MRC-J, a cluster of genes involved in disease resistance. RXC4 was mapped to a 12 cM interval on chromosome II that also contains RXC1, a gene conferring tolerance to X. c. campestris.

Arabidopsis↗
PubMed2003

[Human molecular genetics: from monogenic to polygenic or complex disorders].

Human molecular genetics has successfully identified the genes involved in several monogenic disorders. It now aims at pinpointing the genetic determinants of polygenic or complex traits with a strong genetic component. This constitutes a new challenge. We discuss the methodological and practical aspects of identifying such genes as well as the challenges facing physicians that will have to use efficiently these new diagnostic tools.

Genetic Predisposition to Disease↗
PubMed2004

Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms.

Idiopathic calcium nephrolithiasis is a multifactorial disease with a pathogenesis that involves a complex interaction of environmental and individual factors. This review discusses what is known about monogenic renal calcium stone-related disorders, provides an update on genetic research in calcium nephrolithiasis and such intermediate phenotypes as idiopathic hypercalciuria, discusses the problems that these conditions pose to clinicians and geneticists interested in their pathogenesis, and proposes some method tools potentially useful in this research frame of reference.

Animals↗
PubMed2002

Monogenic forms of human hypertension.

Monogenic or Mendelian forms of hypertension have ushered in a revolution in our knowledge. If we add information on syndromes involving low blood pressure, this knowledge base is doubled. Glucocorticoid-remediable aldosteronism, apparent mineralocorticoid excess, and mutations in the mineralocorticoid receptor gene have given us brilliant insights into mineralocorticoid-induced hypertension. The latter discovery has elucidated how mutations may modify the receptor sufficiently to allow erstwhile antagonists to have an agonistic action. The epithelial sodium channel (ENaC) has been elucidated. Gain-of-function mutations in the beta and gamma subunits of ENaC cause Liddle's syndrome. Loss-of-function mutations in all 3 subunits of ENaC cause hypotension (pseudohypoaldosteronism type I). Thus, all 3 subunits can be mutated, causing either hyper- or hypotension. Three loci have been described for Gordon's syndrome, pseudohypoaldosteronism type II; 2 members of the WNK (with no ly sine K) serine-threonine kinase family have recently been found to be responsible. Autosomal-dominant hypertension with brachydactyly features normal sodium and renin-angiotensin-aldosterone responses. The gene has been mapped to chromosome 12p. The condition is interesting because it may represent a novel neural form of hypertension. The elucidation of Mendelian blood pressure-regulatory disorders has been a resounding success.

Humans↗
PubMed2000

Tachycardia: an autosomal, monogenic, biallelic, recessive trait.

A brief commentary of the genetics of blood pressure is presented. The importance of the mechanisms of blood pressure regulation, among which heart rate is relevant, is emphasized. The analysis of a small population to test the quantitative model of the trait heart rate, considered as a metric character, is presented. The analysis of heart rate fitting to a qualitative model of inheritance is carried out. The results displayed might support the hypothesis that tachycardia could be an autosomal, monogenic, biallelic recessive trait.

Alleles↗
PubMed1987

Bile acid metabolism in hereditary forms of hypertriglyceridemia: evidence for an increased synthesis rate in monogenic familial hypertriglyceridemia.

This study was undertaken to characterize bile acid metabolism in hereditary forms of hypertriglyceridemia. Ten hypertriglyceridemic patients (type IV phenotype) with familial combined hyperlipidemia and 7 patients with monogenic familial hypertriglyceridemia (FHTG) were compared with 18 healthy controls; all subjects were males. Pool size, synthesis rate, and fractional catabolic rate of cholic and chenodeoxycholic acids were determined with an isotope dilution technique. Patients with FHTG had synthesis rates of cholic acid, chenodeoxycholic acid, and total bile acids above those seen in normal controls (P less than 0.001); also the fractional catabolic rates of both bile acids were increased (P less than 0.001). In contrast, bile acid kinetic parameters were--with one exception--within normal limits in patients with familial combined hyperlipidemia. The abnormality of bile acid metabolism could also be identified in a normolipidemic individual presumed to carry the gene for FHTG. The postprandial rise of serum bile acids was blunted in FHTG, indicating that the intestinal uptake of bile acids may be deficient in this condition. We conclude that FHTG, but not familial combined hyperlipidemia, is frequently associated with a defective regulation of bile acid synthesis, resulting in abnormally high production rate of bile acids. It is hypothesized that this abnormality is important for the subsequent development of hypertriglyceridemia.

Adult↗
PubMed2003

Unraveling monogenic channelopathies and their implications for complex polygenic disease.

Ion channels are a large family of >400 related proteins representing >1% of our genetic endowment; however, ion-channel diseases reflect a relatively new category of inborn error. They were first recognized in 1989, with the discovery of cystic fibrosis transmembrane conductance regulator, and rapidly advanced as positional and functional studies converged in the dissection of components of the action potential of excitable tissues. Although it remains true that diseases of excitable tissue still most clearly illustrate this family of disease, ion-channel disorders now cover the gamut of medical disciplines, causing significant pathology in virtually every organ system, producing a surprising range of often unanticipated symptoms, and providing valuable targets for pharmacological intervention. Many of the features shared among the monogenic ion-channel diseases provide a general framework for formulating a foundation for considering their intrinsically promising role in polygenic disease. Since an increasingly important approach to the identification of genes underlying polygenic disease is to identify "functional candidates" within a critical region and to test their disease association, it becomes increasingly important to appreciate how these ion-channel mechanisms can be implicated in pathophysiology.

Animals↗
PubMed2002

Monogene and polygene therapy for the treatment of experimental prostate cancers by use of apoptotic genes bax and bad driven by the prostate-specific promoter ARR(2)PB.

We have shown that adenovirus-mediated manipulation of apoptotic genes such as bax could be a therapeutic option for prostate cancer. Unfortunately, the response of experimental prostate tumors to a single therapeutic gene of the apoptotic pathway is short-lived, and most of these tumors relapse after a short period of time. In this investigation we present data generated with adenovirus AvARR(2)PB-Bad, in which the apoptotic gene bad was placed under the control of the dihydrotestosterone (DHT)-inducible third-generation probasin-derived promoter ARR(2)PB. This therapeutic virus was given alone or in combination with other therapeutic viruses to a variety of in vitro and in vivo experimental models of prostate cancer. On infection with AvARR(2)PB-Bad, DHT-induced Bad overexpression occurred specifically in androgen receptor-positive (AR(+)) cells of prostatic derivation. The apoptotic effect of AvARR(2)PB-Bad (group 1) was compared with that of AvARR(2)PB-Bax (which overexpresses the apoptotic protein Bax) (group 2), with that of the combination AvARR(2)PB-Bad plus AvARR(2)PB-Bax (group 3), and with that of the control virus AvARR(2)PB-CAT (group 4) in the cell line LNCaP. In addition to identifying the modality of apoptosis induction by overexpressed Bad, the results suggested that group 3 contained more apoptotic cells than any other group. In additional studies, AR(+) androgen-dependent LNCaP cells or AR(+) and androgen-independent C4-2 cells were injected subcutaneously into nude mice. Four groups of six LNCaP or C4-2 tumors were treated with the same combinations of viruses discussed above for groups 1, 2, 3, and 4. Treatment resulted in decreased tumor size in groups 1, 2, and 3 compared with group 4. There was a better response in group 3 compared with group 2, and in group 2 compared with group 1. A better response in group 3 was confirmed during a 8-week follow-up period, in which no treatment was administered. Two LNCaP and C4-2 tumors of group 3 disappeared at the end of treatment and did not recur after an 8-week follow-up period. The data suggest that polygene therapy with apoptotic molecules is more effective in experimental models of androgen-dependent or -independent prostate cancer than monogene therapy.

Adenoviridae↗