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PubMed2000

RNA and protein expression of the murine autoimmune regulator gene (Aire) in normal, RelB-deficient and in NOD mouse.

Mutations in the putative transcription factor autoimmune regulator (AIRE) gene are responsible for autoimmune polyendocrinopathy-candidiosis-ectodermal dystrophy (APECED; OMIM#240300), a monogenic recessively inherited disease characterized by destructive autoimmune diseases of the endocrine organs, chronic candidiosis of mucous membranes and ectodermal dystrophies. In this study the expression of murine homolog for AIRE protein, Aire, was detected in a fraction of thymic medullary epithelial cells. Subcellularly, in thymus the protein appears as concentrated into nuclear dot-like structures, whereas in transfected cells the protein is also bound along a cytosolic fibrillar network. By RT-PCR Aire mRNA was detected in thymus, lymph node, spleen and testis although the second round PCR amplified Aire specific band from most mouse tissues analyzed. Furthermore, the Aire mRNA was detected in dendritic cell (DC) populations isolated from thymus and spleen, representing both myeloid- and lymphoid-related lineages of DC. We also demonstrate that the Aire protein is absent in the thymus of RelB-deficient mouse and in NOD thymus most of the Aire positive cells showed an abnormal morphology. These results suggest that the Aire protein is associated with the normal development and/or action of a subset of thymic medullary stromal cells involved in tolerance induction.

Alternative Splicing↗
PubMed1998

The dynamics of globin gene expression and position effects.

We have used gene competition to study the regulation of the human beta-globin locus in transgenic mice as a model system of a multigene locus. The locus is regulated by the locus control region (LCR), which is required for the expression of all the genes. Analysis of the locus at the single-cell level shows that the LCR appears to interact directly with the genes via a looping mechanism. This interaction is monogenic, and the level of transcription is determined by the frequency and stability of LCR/gene complex formation. These parameters are dependent both on the distance between the LCR and gene(s), and the concentration of transcription factors in the nucleus. Disturbance of complex formation leads to position effects, particularly when the locus is integrated in a heterochromatic environment.

Animals↗
PubMed1980

Cleft lip+/-cleft palate: an overview of the literature and an analysis of Danish cases born between 1941 and 1968.

In recent years there has been some controversy over the analytical designs and the meaning of varying results with regard to studies of facial clefting and other common congenital malformations. Regardless, it is still unclear as to the nature of the genetic and environmental components of the etiology as well as the nature of the relevant pathogenetic mechanisms. Despite claims to the contrary, the predictions of a particular multifactorial/threshold inheritance (MF/T) model delineated by Carter [1977d] and others are not well supported by studies worldwide. The present study population consists of 1,895 persons born in Denmark with cleft lip with or without cleft palate (CL +/- P) between 1941 and 1968. A test of the MF/T predictions revealed the following: 1) the incidence of CL +/- P in siblings was 40 X greater than that in the general population 2) the risk to siblings of CL +/- P females was not significantly different from the risk to siblings of CL +/- P males; 3) recurrence risk for siblings of CL +/- P probands was dependent upon the proband's cleft type; 4) only 0.4% of the variation in risk to the siblings born after the proband could be accounted for by the number of previously affected siblings; 5) the consanguinity rate was 6 times less than the general population rate; 6) heritability estimates from siblings and parents by sex suggest, either the presence of significant dominance effects, or a common sibling environment component in the etiology of the disorder. Further, testing with a multiple-sex threshold method, designed and provided us by [Kidd and Spence, 1976] revealed that neither the MF/T nor single-major locus with random environmental variation provided a good fit. In light of recent experimental mouse and human data, an alternative model of monogenic-dependent susceptibility to a variety of teratogens is discussed.

Cleft Lip↗
PubMed1982

Neural tube defects in France: segregation analysis.

Segregation analysis was performed on a subset of a large body of French data comprising 298 nuclear families. Two models were used in this analysis: the transmission probability model [Elston and Stewart, 1971; Elston, 1981] and the mixed model [Morton and MacLean, 1974]. Both models are consistent with familial aggregation of neural tube defects, in this sample, being due to either the segregation of a recessive major gene or a sibling environmental effect, or both factors. In each case, other environmental factors are also involved. These results were compared to the findings of other studies and discussed in respect to the diversity of the epidemiological features displayed by different populations. Some observations of vertical transmission in a British study and the proportion of affected first cousins, in both France and Great Britain, lead us to reject a possible absence of transmission. We propose a monogenic component with a large influence of environmental factors, some of which may be common to sibs, to explain the occurrence of neural tube defects in this sample.

Environment↗
PubMed1985

Congenital anomalies in the Hutterite population: a preliminary survey and hypothesis.

The Alberta Provincial Congenital Anomaly (CA) Surveillance reporting forms were scanned for infants whose surnames and addresses identified them as belonging to the Hutterite Brethren. Death registrations (of infants up to 1 year) and stillbirth registrations were similarly scanned. While the overall percentage of total malformations (5%) and major malformations (2%) was no different from that of the total population of Alberta, closer examination of the actual entities showed a large number of monogenic disorders among the Hutterites. The frequency of multifactorial congenital anomalies was approximately 1%. The inbreeding coefficients, using a genealogic data base, were computed for each "case baby" and two Hutterite "control babies," the latter being births preceding and succeeding the case baby. There was no statistical difference in the distribution of inbreeding coefficients between the case and control groups. While the data are based on small numbers and therefore are preliminary, they suggest that the Hutterite lifestyle, of good nutrition (using largely home prepared foods), absence of tobacco and minimal alcohol consumption, may be one factor responsible for fewer multifactorial CAs whose occurrence is environmentally susceptible to such influences. Studies of populations with a low incidence of disorders are just as important as those with a high incidence.

Alberta↗
PubMed1986

On the genetics of Rett syndrome: analysis of family and pedigree data.

Pedigree studies of 220 Rett syndrome cases (218 isolated cases, one family with affected half sisters and one family with affected sisters) tested 5 monogenic hypotheses, taking account of apparently absolute gynecotropy and healthy parents. Without increased consanguinity we found a normal sex ratio among sibs; the rate of spontaneous abortions was not increased. There is also no increase in parental conceptional age. As the patients do not propagate, transmission of a supposed gene could not be observed. The results are compatible with either an autosomal dominant mutation with complete sex limitation or (more likely) an X-chromosomal dominant mutation with lethality to the males. As the probability for 2 affected sisters in one sibship differs considerably from the real incidence, alternative models should be taken into consideration and may be tested by linkage analysis.

Abortion, Spontaneous↗
PubMed1986

Isolated diaphragmatic defect in three sibs.

We describe three sisters with unilateral agenesis of the diaphragm. No other anomalies were present. As a developmental field defect, diaphragmatic defect is, by definition, causally heterogeneous, and may be seen in several syndromes. Whereas most isolated diaphragmatic defects are likely multifactorially determined, monogenic forms seem to exist.

Congenital Abnormalities↗
PubMedDate not supplied

X-linked mental retardation associated with psoriasis: a new syndrome?

Four males, the sons of 2 sisters, apparently have a new syndrome of mental retardation, seizures and psoriasis. Due to the relationship between the affected males we propose the inheritance to be X-linked recessive although cosegregation of two separate disorders may be occurring. Psoriasis has never been reported as a monogenic disorder. Results of cytogenetic studies, including fra (X) and high-resolution prometaphase analysis, were negative. Steroid sulfatase activities of cultured fibroblasts from 2 surviving affected males were normal. The results of HLA typing of all available relatives did not indicate a strong association between the skin disorder and certain HLA antigens. A healthy sister, who may be heterozygous carrier of the mutant X chromosome, decided on termination of 3 successive pregnancies after prenatal male sex determinations. Her fourth pregnancy with a female fetus is ongoing.

Adult↗
PubMed1988

Craniosynostosis update 1987.

Information on craniosynostosis in this paper updates "Craniosynostosis: Diagnosis, Evaluation, and Management" (Cohen MM Jr: New York: Raven Press, 1986). It also discusses recent developments that were included in the book but need further explanation or emphasis. Subjects discussed are: epidemiology, etiology, sutural biology, growth and development, neurological and psychosocial aspects, surgery, cloverleaf skulls, craniosynostosis syndromes, and prenatal diagnosis. Under the subject of etiology, fetal head constraint, maternal thyroid disease, calcified cephalohematoma, teratogens, and delayed suture closure and Wormian bones are considered. An updating of 15 cloverleaf skull conditions includes four monogenic disorders, two chromosomal disorders, one disruption, one iatrogenic condition, and seven syndromes of unknown cause. Newly recognized disorders with cloverleaf skull include Beare-Stevenson cutis gyratum syndrome and Say-Poznanski syndrome. Craniosynostosis syndromes and associations discussed include acrocraniofacial dysostosis, Apert syndrome, Beare-Stevenson cutis gyratum syndrome, Calabro syndrome, calvarial hyperostosis, chromosomal craniostenosis, Cole-Carpenter type osteogenesis imperfecta, Crouzon syndrome, Curry-Jones syndrome, Curry variant of Carpenter syndrome, cutis aplasia and cranial stenosis, Fontaine-Farriaux syndrome, Gomex-López-Hernández syndrome, Hersh syndrome, hyper-IgE syndrome and craniostenosis, hypomandibular faciocranial dysostosis, Marfanoid features and craniostenosis, Pfeiffer-type cardiocranial syndrome, Pfeiffer-type dolichocephalosyndactyly, and Say-Barber syndrome.

Animals↗
PubMed1989

Mutation rate estimates are not compatible with autosomal dominant inheritance of the dysplastic nevus "syndrome".

Dysplastic nevi represent precursor lesions harboring an increased risk of evolving into melanoma. Their association with familial melanoma is usually considered a monogenic syndrome with autosomal dominant transmission. To test this concept we estimated the mutation rates. When derived directly from the sporadic occurrence of the trait, the mutation rate is exceedingly high (0.9%-2.5%), whereas, as estimated with the aid of Haldane's formula it would be 0.007% to 0.02%. Accordingly, newly arising mutation would outnumber eliminated mutations by 100:1. Even if only 80% of all old mutations are passed onto the next generation, this ratio of 100:1 would rapidly change. After only a few generations, 10% of the world population should be affected with the dysplastic nevus "syndrome". The apparent lack of a genetic equilibrium between newly arising and eliminated mutations is not compatible with autosomal dominant inheritance of the dysplastic nevus "syndrome."

Chromosome Aberrations↗
PubMed1990

Clinical/epidemiological analysis of malformations.

To investigate the heterogeneity of congenital malformations, we analyzed the distribution of 14 selected anomalies among 11,421 children with isolated defects and with different patterns of multiple congenital anomalies (MCA). Our study showed a marked variability in the distribution of each of these malformations. For example, although anophthalmia/microphthalmia, cleft palate, and limb deficiency were observed in all etiological categories of syndromes, no case with anencephaly was identified among the 1,244 children with different syndromes. Diaphragmatic hernia, esophageal atresia +/- tracheoesophageal fistula, and gastroschisis were not found in any monogenic syndrome in this sample. These observations may be of help to the clinician in the evaluation of individual children with MCA.

Abnormalities, Multiple↗
PubMed1990

Myelodysplasia and leukemia syndrome with monosomy 7: a genetic perspective.

Acquired monosomy 7 is a frequent finding in myelodysplastic syndromes, including acute myelogenous leukemia. A subset of these patients has been described with an apparently distinct condition: myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7). We report 2 brothers, 3 and 5 years of age, with MLSM7 and review other reports of familial occurrence. Genetic factors appear to be important in the cause of MLSM7, but the reported families do not fit neatly into any monogenic pattern. Recognition of the frequently familial nature of this condition requires hematological evaluation and genetic counseling for the families of patients with MLSM7.

Adolescent↗
PubMed1990

Familial sex chromosomal mosaicism.

Familial mosaicism has rarely been reported either for autosomes or sex chromosomes. Its recognition poses problems in prognosis, especially in prenatal diagnosis. Three generations of females showed sex chromosomal mosaicism with 3-4 cell lines, the diploid predominant. Phenotypic effect, if any, appeared limited to reduced fertility. The proposita, ascertained prenatally, has grown and developed normally. A dominant gene mechanism most likely accounts for the observations, either autosomal or X-linked. If the mechanism in this family is monogenic, then the gene may not be strictly private considering the frequency of mosaic amniotic fluid cell cultures.

Adult↗
PubMed1993

Provisionally unique autosomal recessive chondrodysplasia punctata syndrome.

Stippled epiphyses occur in several monogenic, teratogenic, or aneuploidy syndromes. We describe two sibs with a provisionally unique chondrodysplasia punctata syndrome, who have, in addition to stippled epiphyses, minor facial anomalies, short stature, and ocular colobomata. Inheritance of this condition is likely autosomal recessive.

Abnormalities, Multiple↗
PubMed1995

Genetic threshold hypothesis of neocortical spike-and-wave discharges in the rat: an animal model of petit mal epilepsy.

Neocortical high-voltage spike-and-wave discharges (HVS) in the rat are an animal model of petit mal epilepsy. Genetic analysis of total duration of HVS (s/12 hr) in reciprocal F1 and F2 hybrids of F344 and BN rats indicated that the phenotypic variability of HVS cannot be explained by a simple, monogenic Mendelian model. Biometrical analysis suggested the presence of additive, dominance, and sex-linked-epistatic effects, buffering maternal influence, and heterosis. High correlation was observed between average duration (s/episode) and frequency of occurrence of spike-and-wave episodes (n/12 hr) in parental and segregating generations, indicating that common genes affect both duration and frequency of the spike-and-wave pattern. We propose that both genetic and developmental-environmental factors control an underlying quantitative variable, which, above a certain threshold level, precipitates HVS discharges. These findings, together with the recent availability of rat DNA markers for total genome mapping, pave the way to the identification of genes that control the susceptibility of the brain to spike-and-wave discharges.

Action Potentials↗
PubMed2001

Genetic variation of the human glycine receptor subunit genes GLRA3 and GLRB and susceptibility to idiopathic generalized epilepsies.

Alterations of glycine receptor alpha1 and beta subunit genes have been associated with hypertonic motor disorders in both mice and humans. Mutations in genes encoding other ligand- and voltage-gated ion channels have been identified in rare monogenic forms of idiopathic generalized epilepsies (IGE). We tested the hypothesis that allelic variants of the glycine receptor subunit genes, GLRA3 and GLRB, both localized on chromosome 4q, confer susceptibility to common subtypes of IGE. Mutation screening was carried out in index patients of 14 IGE families. No pathogenic mutation was found, but two intronic polymorphisms were detected in the GLRB gene, and four intronic, three exonic, and one 3'-UTR polymorphisms were identified for the GLRA3 gene. Subsequent screening for exonic and 3'-UTR polymorphisms in GLRA3 showed no statistical difference between a group of sporadic IGE patients (n = 104) and a control group (n = 141). The genotype frequencies for exonic and 3'-UTR polymorphisms in GLRA3 showed no statistically significant difference between IGE patients (n = 104) and an ethnically matched control group (n = 141). Thus, no association between IGE and alterations in GLRA3 or GLRB genes could be detected, indicating that both genes do not play a major causative role in the epileptogenesis of common IGE subtypes. Still, these novel single nucleotide polymorphisms may be useful markers for candidate gene analyses of other disorders.

Alleles↗
PubMed2005

Congenital stationary night blindness: report of an autosomal recessive family and linkage analysis.

Congenital stationary night blindness (CSNB) is a group of rare, non-progressive conditions of the retina characterized by abnormal rod function causing impaired night vision. Among them, the Schubert-Bornschein subgroup, itself divided into a complete and an incomplete form, is characterized by a specific electrophysiological pattern. Complete, Schubert-Bornschein CSNB is usually transmitted as a monogenic trait, and most familial cases result from mutations of the NYX gene located on the X chromosome. We report a very rare family with consanguineous, first-cousin parents, where a son and a daughter are affected with this condition, indicating autosomal recessive inheritance. As the family was too small for genome-wide linkage, we considered several candidate loci, including the sidekick SDK1 and SDK2 genes. The latter determine lamina-specific connectivity in the retina, a histological substrate of the ON pathway implicated in complete, Schubert-Bornschein CSNB. Although linkage was excluded in our family, observations like the present one may lead to the identification of a new molecular cause for this condition.

Child, Preschool↗
PubMed2005

Autosomal dominant inheritance of left ventricular outflow tract obstruction.

Most nonsyndromic congenital heart malformations (CHMs) in humans are multifactorial in origin, although an increasing number of monogenic cases have been reported recently. We describe here four new families with presumed autosomal dominant inheritance of left ventricular outflow tract obstruction (LVOTO), consisting of hypoplastic left heart (HLHS) or left ventricle (HLV), aortic valve stenosis (AS) and bicuspid aortic valve (BAV), hypoplastic aortic arch (HAA), and coarctation of the aorta (CoA). LVOTO in these families shows a wide clinical spectrum with some family members having severe anomalies such as hypoplastic left heart, and others only minor anomalies such as mild aortic valve stenosis. This supports the suggestion that all anomalies of the LVOTO spectrum are developmentally related and can be caused by a single gene defect.

Animals↗