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PubMed2005

Cellular inheritance of a Cre-activated reporter gene to determine Paneth cell longevity in the murine small intestine.

Here, we exploit an absolute differential between stem and progeny cells in their ability to express Cre from a somatically inducible transgene to determine the longevity of intestinal Paneth cells. In the Ahcre transgenic line induction of Cre recombinase allows constitutive activation of a Cre-activated reporter in intestinal precursors but not in Paneth cells. The time taken for Paneth cells to inherit the reporter (EYFP) was measured in adult Ahcre/R26R-EYFP animals. Using confocal microscopy of TOPRO-3-stained sections, both precursors and Paneth cells were identified and subsequently scored for EYFP expression. It takes up to 57 days for Paneth cells to inherit the reporter, making them three times longer-lived than previously indicated using nucleotide incorporation and suggesting that such determinations of cell turnover may be significant underestimates.

Animals↗
PubMed1992

Inheritance of the group I rDNA intron in Tetrahymena pigmentosa.

We have previously argued from phylogenetic sequence data that the group I intron in the rRNA genes of Tetrahymena was acquired by different Tetrahymena species at different times during evolution. We have now approached the question of intron mobility experimentally by crossing intron+ and intron- strains looking for a strong polarity in the inheritance of the intron (intron homing). Based on the genetic analysis we find that the intron in T. pigmentosa is inherited as a neutral character and that intron+ and intron- alleles segregate in a Mendelian fashion with no sign of intron homing. In an analysis of vegetatively growing cells containing intron+ and intron- rDNA, initially in the same macronucleus, we similarly find no evidence of intron homing. During the course of this work, we observed to our surprise that progeny clones from some crosses contained three types of rDNA. One possible explanation is that T. pigmentosa has two rdn loci in contrast to the single locus found in T. thermophila. Some of the progeny clones from the genetic analysis were expanded for several hundred generations, and allelic assortment of the rDNA was demonstrated by subcloning analysis.

Alleles↗
PubMed1995

A novel strategy to identify maternal and paternal inheritance in the mouse.

A novel strategy for identifying proteins which reveal maternal or paternal inheritance in the mouse is presented. Using two-dimensional electrophoresis we investigated protein expression patterns of adult liver and different embryonic and extraembryonic tissue in C57BL/6Crl and in DBA/2Crl mice, as well as in their reciprocal hybrids. We found three groups of protein spots which showed maternal or paternal inheritance of quantitative variations. These proteins were characterized by N-terminal or internal amino acid sequencing, by determination of the amino acid composition, by glycoprotein staining and RNA expression analysis. The three proteins identified were: alpha-enolase, cyclophilin and beta-group hemoglobins. The parental effects observed for alpha-enolase and cyclophilin were found to be due to parent-specific post-translational modifications of these proteins. For the beta-group hemoglobins our results suggested parental effects on the transcriptional level.

Amino Acid Isomerases↗
PubMed2003

Maternal inheritance of Cre activity in a Sox2Cre deleter strain.

The Sox2 gene is expressed in several undifferentiated cell types. In an earlier study we described a Sox2Cre transgene that mediates epiblast-specific Cre-mediated modification of gene activity in the embryo. Here we report that this transgene is active in the female germline. Consequently, all offspring that arise from female mice heterozygous for the Sox2Cre transgene have demonstrable Cre activity irrespective of whether they inherit the transgene itself. Maternal inheritance of Cre activity allows the efficient modification of gene activity for functional analysis.

Alleles↗
PubMed1985

A new model for the resolution of cultural and biological inheritance in the presence of temporal trends: application to systolic blood pressure.

A contemporary path model for the resolution of cultural and biological inheritance is extended to incorporate temporal variation in family resemblance. Specifically, the genetic and environmental effects, like all other parameters of the model, are allowed to vary over an individual's age according to some specific mathematical functions. In the computer program BETREND a library of such functions is incorporated. Data on systolic blood pressure in 542 Japanese-American nuclear families were analyzed. This new methodology detected significant temporal variation in cultural inheritance, a result that was not found previously by using static models which could only distinguish between adult and childhood heritabilities. Cultural heritability, estimated to be 10% at birth, increases to a maximum of 28% at age 36, at which time it declines until it eventually reaches 10% at age 49. Although not statistically significant, there was some evidence for temporal trends in genetic heritability as well. Ignoring trends, the genetic heritability was estimated as .30. On the other hand, trends in sibling environment were clearly nonsignificant. This model provides an objective method of testing the significance of temporal trends in familial resemblance by using multifactorial models, of resolving varying gene expression and transient environmental effects as possible sources of generating the observed temporal variation, and of estimating continuous changes in heritability with age.

Adolescent↗
PubMed1987

Early onset periodontitis: a comparison and evaluation of two proposed modes of inheritance.

Two rare types of familial periodontitis, a localized form usually diagnosed in late adolescence, and a more generalized form with a latter mean age of diagnosis, have been analyzed with respect to genetic models currently favored in the dental literature. These include autosomal recessive and X-linked dominant (partial penetrance) inheritance. Since there is variation in severity, extent, age of onset, altered sex ratio of affected individuals, and a low population prevalence, it is not surprising that genetic mechanisms heretofore have not been revealed. We have compared the likelihoods of 33 kindreds ascertained through affected probands under the above genetic models. Our findings include (1) several families in which both forms of early onset periodontitis co-occur, making it unlikely that the clinical varieties of the disease have unrelated genetic causes; (2) the autosomal recessive model is far more likely than the X-linked dominant model. The superiority of the recessive hypothesis arises from the fact that there are only a few instances of affected individuals having affected parents and because the skewed sex ratio is shown to be incompatible with X-linked inheritance. These conclusions are largely insensitive to the assumptions of the analysis. We conclude that the X-linked dominant hypothesis is inadequate, and while the autosomal recessive model is by no means proven, it is clearly favored.

Adolescent↗
PubMed2003

A novel mutation in the SDHD gene in a family with inherited paragangliomas--implications of genetic diagnosis for follow up and treatment.

BACKGROUND: Early detection of paragangliomas (PGs) has been linked to low morbidity after surgical resection. Recent identification of causative genes (SDHB, SDHC, and SDHD) has made it possible to detect individuals at high risk for tumors. METHODS: We identified a three-generation family, with four individuals affected with PGs. Because pedigree analysis suggested maternal imprinting (the phenotype is present only if inherited through the paternal line), the SDHD gene (PGL1) was screened. RESULTS: A novel mutation that causes skipping of exon 3 was identified. Ten of the seventeen tested individuals carried the mutation. All six clinically unaffected individuals inherited the mutation from their mother. Five of them are men, with a 50% risk for affected progeny. CONCLUSIONS: To allow early treatment with low morbidity, genetic counseling is needed when familial paraganglioma is suspected. Asymptomatic carriers should be followed by cervical MRI. In addition, because pheochromocytomas may occur, catecholamine excretion can be performed. This screening should probably be proposed at 5 to 10 years of age.

Adult↗
PubMed2003

Translocation and gross deletion breakpoints in human inherited disease and cancer I: Nucleotide composition and recombination-associated motifs.

Translocations and gross deletions are important causes of both cancer and inherited disease. Such gene rearrangements are nonrandomly distributed in the human genome as a consequence of selection for growth advantage and/or the inherent potential of some DNA sequences to be frequently involved in breakage and recombination. Using the Gross Rearrangement Breakpoint Database [GRaBD; www.uwcm.ac.uk/uwcm/mg/grabd/grabd.html] (containing 397 germ-line and somatic DNA breakpoint junction sequences derived from 219 different rearrangements underlying human inherited disease and cancer), we have analyzed the sequence context of translocation and deletion breakpoints in a search for general characteristics that might have rendered these sequences prone to rearrangement. The oligonucleotide composition of breakpoint junctions and a set of reference sequences, matched for length and genomic location, were compared with respect to their nucleotide composition. Deletion breakpoints were found to be AT-rich whereas by comparison, translocation breakpoints were GC-rich. Alternating purine-pyrimidine sequences were found to be significantly over-represented in the vicinity of deletion breakpoints while polypyrimidine tracts were over-represented at translocation breakpoints. A number of recombination-associated motifs were found to be over-represented at translocation breakpoints (including DNA polymerase pause sites/frameshift hotspots, immunoglobulin heavy chain class switch sites, heptamer/nonamer V(D)J recombination signal sequences, translin binding sites, and the chi element) but, with the exception of the translin-binding site and immunoglobulin heavy chain class switch sites, none of these motifs were over-represented at deletion breakpoints. Alu sequences were found to span both breakpoints in seven cases of gross deletion that may thus be inferred to have arisen by homologous recombination. Our results are therefore consistent with a role for homologous unequal recombination in deletion mutagenesis and a role for nonhomologous recombination in the generation of translocations.

Alu Elements↗
PubMed2004

Transfer of a mitochondrial DNA fragment to MCOLN1 causes an inherited case of mucolipidosis IV.

A patient with mucolipidosis-IV heterozygous for two mutations in MCOLN1 expressed only her father's cDNA mutation c.1207C>T predicting an R403C change in mucolipin. She inherited a 93bp segment from mitochondrial NADH dehydrogenase 5 (MTND5) from her mother that was inserted in-frame prior to the last nucleotide of exon 2 of MCOLN1 (c.236_237ins93). This alteration abolished proper splicing of MCOLN1. The splice site at the end of the exon was not used due to an inhibitory effect of the inserted segment, resulting in two aberrant splice products containing stop codons in the downstream intron. These products were eliminated via nonsense-mediated decay. This is the first report of an inherited transfer of mitochondrial nuclear DNA causing a genetic disease. The elimination of the splice site by the mitochondrial DNA requires a change in splicing prediction models.

Base Sequence↗
PubMed2005

Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare disorder caused by mutations in the autoimmune regulator gene (AIRE) and characterized by a variable combination of organ-specific autoimmune diseases. Studies on AIRE-deficient mice suggest that AIRE is an important factor in the establishment and maintenance of self-tolerance. The AIRE protein contains several structural domains often found in transcriptional regulators and functions as a transcriptional transactivator in vitro. To date, more than 50 patient mutations have been identified in the coding region of the AIRE gene. So far, APECED has been reported to be inherited in an autosomal recessive manner. However, in contrast to all other AIRE mutations, a novel mutation c.682T>G (p.G228W) in the DNA-binding and/or multimerization domain SAND was recently described to be inherited in a dominant fashion. We analyzed the effects of mutant AIRE proteins containing the patient mutations c.682T>G (p.G228W) and c.755C>T (p.P252L) located in the SAND domain on the properties of the wild-type AIRE in a heterozygous situation in vitro. In addition to the patient mutations, we analyzed the effects of a double mutation [c.727A>G;c.728A>C;c.739C>G;c740G>C] (p.K243A;R247A) of positively charged amino acids in the SAND domain. Of the mutants studied, only c.682T>G (p.G228W) mutant changed the subcellular localization and in addition severely disrupted the transactivating capacity of the wild-type AIRE. Our results indicate that the c.682T>G (p.G228W) mutant AIRE protein acts with a dominant negative effect by binding to the wild-type AIRE, thus preventing the protein from forming the complexes needed for transactivation.

Animals↗
PubMed1990

The developmental fate of fission yeast cells is determined by the pattern of inheritance of parental and grandparental DNA strands.

A key feature for development consists of producing sister cells that differ in their potential for cellular differentiation. Following two cell divisions, a haploid Schizosaccharomyces pombe cell produces one cell in four 'granddaughters' with a changed mating cell type, implying nonequivalence of sister cells in each of two consecutive cell divisions. The observed pattern of switching is analogous to the mammalian 'stem cell' lineage by which a cell produces one daughter like itself while the other daughter is advanced in its developmental program. It is tested here whether sisters differ because of unequal distribution of cytoplasmic and/or nuclear components to them or due to inheriting a specific parental DNA chain at the mating type locus. Only the DNA strand-segregation model predicts that those cells engineered to contain an inverted tandem duplication of the mating type locus should produce equivalent sisters. Consequently, two 'cousins' in four related granddaughter cells should switch. The results verified the prediction, thus establishing that all cells otherwise fully possess the potential to switch. Therefore, the program of cell type change in S.pombe cell lineages is determined by the pattern of DNA strand inheritance at the mating type locus. A specific DNA sequence present at the mating type locus is postulated to be the cause of developmental asymmetry between sister cells. A general model for cellular differentiation is proposed in which the act of DNA replication itself is hypothesized to produce developmentally nonequivalent sister genomes.

DNA, Fungal↗
PubMed1991

Gyrase-dependent stabilization of pSC101 plasmid inheritance by transcriptionally active promoters.

The pSC101 plasmid encodes a cis-acting genetic locus termed par that ensures the stable inheritance of plasmids in a population of dividing cells. In the absence of selection, par-defective plasmids are lost rapidly from the bacterial population. We report here that the stability of par-deleted pSC101 derivatives is restored by introducing certain adventitious bacterial promoters onto the plasmid. Stabilization requires active transcription from the inserted promoter and is affected by the site and orientation of the insertion, the length of the nascent transcript and DNA gyrase activity. While a promotor-associated overall increase in negative superhelicity of plasmid DNA was observed, stabilized inheritance appeared to be dependent on localized rather than generalized supercoiling. Our demonstration that promoter-induced DNA supercoiling can mimic the effects of the pSC101 par locus provides evidence that the previously reported superhelicity-generating effects of par are intrinsic to its function.

DNA Topoisomerases, Type II↗
PubMed2002

Hematopoietic stem cell gene therapy for inherited bone marrow disorders: past accomplishments and continued challenges.

From the time that the genes encoding the defective proteins were cloned for a number of inherited diseases, it became a goal to correct those conditions by restoring the normal gene and thereby, its product. For the inherited disorders affecting the blood and its progenitor cells, the hematopoietic stem cells were the ideal target cells for gene transfer, because the normal gene would then be transferred to all of the progeny cells, theoretically for the lifetime of the recipient. However, the tasks of isolating the hematopoietic stem cells, introducing the new genes in such a manner as to preserve engraftment of the manipulated cells, and achieving long-term gene expression, have not been straightforward in the clinical trial setting, although there has been moderate success for cells in vitro, and in murine studies. With the report of clinical efficacy of gene transfer in children with X-linked severe combined immunodeficiency disease, the dream of clinical gene transfer to hematopoietic cells has become a reality. But there are still significant impediments remaining for a number of diseases. The innovations of introduction of synthetic receptors that confer growth advantage, the use of lentiviral vectors with increased stem cell transduction efficiency, and the addition of modified promoter/enhancer sequences to augment and preserve gene expression may bring wider success to gene therapy clinical trials for bone marrow disorders in the near future.

Animals↗
PubMed1991

Patterns of transgene inheritance in rainbow trout (Oncorhynchus mykiss).

There have been very few studies of the inheritance of introduced genes (transgenes) in fish. We have followed the inheritance of the mammalian fusion gene MTrGH from founder generation transgenics (originating from eggs microinjected with the MTrGH DNA) to offspring in crosses with control fish. Initial screening of the founder generation transgenics was by analysing DNA from blood samples. Only three out of six fish which carried the novel gene in blood DNA transmitted it to their offspring, despite the presence of the gene in DNA extracted from the sperm of all four male fish in this group. The frequency of transgenics in the progeny groups from the three fish which transmitted the gene varied widely: in one of these groups more than one type of MTrGH restriction pattern was found. These results suggest widespread mosaicism in founder generation transgenics.

Animals↗
PubMed1990

Schwartz-Jampel syndrome with dominant inheritance.

The Schwartz-Jampel syndrome (SJS) is a rare congenital multisystem disorder of unknown pathogenesis which is characterized by distinct faces, skeletal deformities, joint contractures, short stature, muscle hypertrophy, clinical myotonia, and continuous muscle fiber activity. The inheritance pattern of SJS has been assumed to be autosomal recessive. We report the occurrence of the classic SJS syndrome in both a father and son in a non-consanguineous family, suggesting that SJS has the potential for a dominant pattern of inheritance.

Adult↗
PubMed1993

Screening of dominantly inherited Charcot-Marie-Tooth neuropathies.

Sixty-three families with dominantly inherited Charcot-Marie-Tooth (CMT) neuropathies including 730 subjects (total) from which 356 affected were studied clinically, electrophysiologically (MNCVs and EMGs), by genetic linkage, and screened for DNA duplication. Thirty-eight families (60.3%) were type 1A (demyelinating CMT mapped on chromosome 17). DNA duplication was present in 36 families (94.8% of CMT1A families). One CMT1A family (2.6%) showed no duplication but suggested genetic linkage with markers of chromosome 17. One CMT1A family (2.6%) revealed nonduplication in some affected members and duplication in other affected members. The disease in that family segregated with the same chromosome 17 markers regardless of duplication status. The other CMT families with dominant inheritance but without duplication included one family with CMT1B (demyelinating CMT mapped on chromosome 1) (1.6%), 14 families with CMT2 axonal neuropathy (22.2%), and 10 families with X-linked dominant CMT (15.9%).

Action Potentials↗
PubMed1995

Mitochondrial encephalomyopathy with autosomal dominant inheritance: a clinical and genetic entity of mitochondrial diseases.

We report a Japanese family with chronic progressive external ophthalmoplegia (CPEO) with autosomal dominant inheritance, and review 54 reported CPEO patients in seven families (including the present family) with autosomal dominant inheritance and mtDNA deletions in the skeletal muscle. Mean age at onset in the CPEO was 26 years, which is older than that in published solitary cases. In addition to blepharoptosis and external opthalmoplegia, proximal muscle atrophy and weakness were found in 62%, hearing loss in 25%, and ataxia in 17% of the patients. Retinal degeneration was not found, and cardiac involvement was very rare. mtDNA deletions in the muscle were multiple and large scale, and all such deletions were located in the non-D-loop region. Autosomal dominant CPEO has unique clinical features which differ from those of solitary CPEO, and is associated with multiple large-scale mtDNA deletions. Thus, autosomal dominant CPEO can be considered a clinical and genetic entity of mitochondrial diseases.

Base Sequence↗
PubMed2006

Inherited predispositions and hyperactive Ras in myeloid leukemogenesis.

Identifying the molecular basis for inherited cancer predispositions reveals genes that when mutated, play a critical role in the earliest stages of tumorigenesis. Although rare, inherited predispositions to myeloid leukemias have led to a greater understanding of pathways important for myeloid proliferation and maturation. In particular, elucidating why children with neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are predisposed to juvenile myelomonocytic leukemia (JMML) has uncovered a critical role of hyperactive Ras signaling in normal myeloid growth and leukemogenesis. Here, we review studies of human samples and experiments performed in genetically engineered strains of mice investigating the molecular and biochemical basis of aberrant growth in JMML. These strains model human disease features and provide an opportunity to investigate novel therapeutic strategies that may ultimately cure JMML and other myeloid malignancies characterized by hyperactive Ras.

Animals↗