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PubMed1998

Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis.

Aceruloplasminemia is an autosomal recessive disorder characterized by progressive neurodegeneration of the retina and basal ganglia associated with specific inherited mutations in the ceruloplasmin gene. Clinical and pathologic studies in patients with aceruloplasminemia revealed a marked accumulation of iron in affected parenchymal tissues, a finding consistent with early work identifying ceruloplasmin as a ferroxidase and with recent findings showing an essential role for a homologous copper oxidase in iron metabolism in yeast. The presence of neurologic symptoms in aceruloplasminemia is unique among the known inherited and acquired disorders of iron metabolism; recent studies revealed an essential role for astrocyte-specific expression of ceruloplasmin in iron metabolism and neuronal survival in the central nervous system. Recognition of aceruloplasminemia provides new insights into the genetic and environmental determinants of copper metabolism and has important implications for our understanding of the role of copper in human neurodegenerative diseases.

Ceruloplasmin↗
PubMed2004

Decisions and outcomes of genetic testing for inherited breast cancer risk.

Since the discovery of breast cancer susceptibility genes and the availability of genetic testing, a substantial amount of research has been conducted to evaluate rates of genetic test acceptance and to understand the psychological and behavioral impact of BRCA1 and BRCA2 (BRCA1/2) genetic test results. This article explores findings related to genetic test acceptance for inherited breast cancer risk and the impact of genetic test results on psychological functioning, cancer prevention and control behaviors, and family communication about genetic testing. Overall, rates of genetic test acceptance were lower than anticipated based on interest in genetic testing reported in early research. While there is limited evidence that genetic testing generates adverse psychological effects, receiving positive BRCA1/2 test results may cause emotional reactions and concerns that are specific to such results. Although early reports suggested that receiving positive BRCA1/2 test results may have a limited impact on cancer screening or prevention behaviors, recent studies have shown that genetic testing for inherited breast cancer risk may increase screening behaviors among mutation carriers. However, utilization of some screening tests remains low among mutation carriers. Additional studies are needed to identify subgroups of participants in genetic testing who may be vulnerable to experiencing testing-specific concerns, and to evaluate the effects of interventions designed to promote behavioral change and address other concerns that may be generated by receiving positive BRCA1/2 test results.

BRCA1 Protein↗
PubMed2004

Morphological features and inheritance of Foliaceous Stipules of primary leaves in cowpea (Vigna unguiculata).

BACKGROUND AND AIMS: The presence of connate foliaceous stipules of primary leaves and their inheritance in cowpea (Vigna unguiculata) genotype EC394736 is reported for the first time. METHODS: The development of foliaceous stipules (FS) and their persistence were examined throughout the growth and developmental stages of the plants of the genotype EC394736. The shape, size, colour, texture and other parameters were examined in the field during the period 15-50 d after sowing. The area of FS was measured using image analysis software. The inheritance of FS was studied by making a cross between the genotype EC394763 with rudimentary stipules (RS) and the genotype EC394736, which has connate foliaceous stipules of primary leaves. The presence or absence of FS in plants of the F1, F2 and F3 generations was recorded. KEY RESULTS: The stipules developed along with the primary leaves in the genotype EC394736. One stipule of each primary leaf fused with the adjacent stipule of the other primary leaf forming a foliaceous structure. These stipules persisted on the plants for >50 d, even after the primary leaves had withered off. The F1 plants showed an absence of FS indicating the rudimentary stipules to be dominant over foliaceous stipules. The F2 segregation into 15 (RS) : 1 (FS) indicated that duplicate recessive genes controlled the presence of the FS. This was confirmed from the segregation pattern in the F3 generation. CONCLUSIONS: The presence of FS is a unique feature in cowpea genotype EC394736 and duplicate recessive genes govern it. The FS can be used as a morphological marker for identification of cowpea varieties.

Crosses, Genetic↗
PubMed1992

Inherited prion disease with 144 base pair gene insertion. 2. Clinical and pathological features.

A large family with autosomal dominant segregation of presenile dementia, and other neurological and behavioural features is described. At various times, family members have carried diagnoses of Alzheimer's disease, Huntington's disease, Parkinson's disease, myoclonic epilepsy, atypical dementia, Pick's disease, Creutzfeldt-Jakob disease and Gerstmann-Sträussler syndrome. Molecular genetic studies have enabled classification of this disease at the molecular level as one of the group of inherited prion diseases. Here we describe the phenotype of inherited prion disease (PrP 144 bp insertion).

Adult↗
PubMed2006

Phenotypic heterogeneity in inherited prion disease (P102L) is associated with differential propagation of protease-resistant wild-type and mutant prion protein.

Inherited prion diseases are caused by PRNP coding mutations and display marked phenotypic heterogeneity within families segregating the same pathogenic mutation. A proline-to-leucine substitution at prion protein (PrP) residue 102 (P102L), classically associated with the Gerstmann-Sträussler-Scheinker (GSS) phenotype, also shows marked clinical and pathological heterogeneity, including patients with a Creutzfeldt-Jakob disease (CJD) phenotype. To date, this heterogeneity has been attributed to temporal and spatial variance in the propagation of distinct protease-resistant (PrP(Sc)) isoforms of mutant PrP. Here, using a monoclonal antibody that recognizes wild-type PrP, but not PrP 102L, we reveal a spectrum of involvement of wild-type PrP(Sc) in P102L individuals. PrP(Sc) isoforms derived from wild-type and mutant PrP are distinct both from each other and from those seen in sporadic and acquired CJD. Such differential propagation of disease-related isoforms of wild-type PrP and PrP 102L provides a molecular mechanism for generation of the multiple clinicopathological phenotypes seen in inherited prion disease.

Adult↗
PubMed1996

Inheritance of mitochondrial DNA and plasmids in the ascomycetous fungus, Epichloë typhina.

We analyzed the inheritance of mitochondrial DNA (mtDNA) species in matings of the grass symbiont Epichloë typhina. Eighty progeny were analyzed from a cross in which the maternal (stromal) parent possessed three linear plasmids, designated Callan-a (7.5 kb), Aubonne-a (2.1 kb) and Bergell (2.0 kb), and the paternal parent had one plasmid, Aubonne-b (2.1 kb). Maternal transmission of all plasmids was observed in 76 progeny; two progeny possessed Bergell and Callan-a, but had the maternal Aubonne-a replaced with the related paternal plasmid Aubonne-b; two progeny lacked Callan-a, but had the other two maternal plasmids. A total of 34 progeny were analyzed from four other matings, including a reciprocal pair, and in each progeny the plasmid transmission was maternal. The inheritance of mitochondrial genomes in all progeny was analyzed by profiles of restriction endonuclease-cleaved mtDNA. In most progeny the profiles closely resembled those of the maternal parents, but some progeny had nonparental mtDNA profiles that suggested recombination of mitochondrial genomes. These results indicate that the fertilized stroma of E. typhina is initially heteroplasmic, permitting parental mitochondria to fuse and their genomes to recombine.

Ascomycota↗
PubMed1996

Maximum likelihood analysis of rare binary traits under different modes of inheritance.

Maximum likelihood methodology was applied to determine the mode of inheritance of rare binary traits with data structures typical for swine populations. The genetic models considered included a monogenic, a digenic, a polygenic, and three mixed polygenic and major gene models. The main emphasis was on the detection of major genes acting on a polygenic background. Deterministic algorithms were employed to integrate and maximize likelihoods. A simulation study was conducted to evaluate model selection and parameter estimation. Three designs were simulated that differed in the number of sires/number of dams within sires (10/10, 30/30, 100/30). Major gene effects of at least one SD of the liability were detected with satisfactory power under the mixed model of inheritance, except for the smallest design. Parameter estimates were empirically unbiased with acceptable standard errors, except for the smallest design, and allowed to distinguish clearly between the genetic models. Distributions of the likelihood ratio statistic were evaluated empirically, because asymptotic theory did not hold. For each simulation model, the Average Information Criterion was computed for all models of analysis. The model with the smallest value was chosen as the best model and was equal to the true model in almost every case studied.

Algorithms↗
PubMed1998

Inherited and environmentally induced differences in mutation frequencies between wild strains of Sordaria fimicola from "Evolution Canyon".

We have studied whether there is natural genetic variation for mutation frequencies, and whether any such variation is environment-related. Mutation frequencies differed significantly between wild strains of the fungus Sordaria fimicola isolated from a harsher or a milder microscale environment in "Evolution Canyon," Israel. Strains from the harsher, drier, south-facing slope had higher frequencies of new spontaneous mutations and of accumulated mutations than strains from the milder, lusher, north-facing slope. Collective total mutation frequencies over many loci for ascospore pigmentation were 2.3, 3.5 and 4.4% for three strains from the south-facing slope, and 0.9, 1.1, 1.2, 1.3 and 1.3% for five strains from the north-facing slope. Some of this between-slope difference was inherited through two generations of selfing, with average spontaneous mutation frequencies of 1.9% for south-facing slope strains and 0.8% for north-facing slope strains. The remainder was caused by different frequencies of mutations arising in the original environments. There was also significant heritable genetic variation in mutation frequencies within slopes. Similar between-slope differences were found for ascospore germination-resistance to acriflavine, with much higher frequencies in strains from the south-facing slope. Such inherited variation provides a basis for natural selection for optimum mutation rates in each environment.

Acriflavine↗
PubMed1998

Gene silencing by DNA methylation and dual inheritance in Chinese hamster ovary cells.

Chinese hamster ovary (CHO) cells strain D422, which has one copy of the adenine phosphoribosyl transferase (APRT) gene, were permeabilized by electroporation and treated with 5-methyl deoxycytidine triphosphate. Cells with a silenced APRT gene were selected on 2, 6-diaminopurine. Colonies were isolated and shown to be reactivated to APRT+ by 5-aza-cytidine and by selection in medium containing adenine, aminopterin and thymidine. Genomic DNA was prepared from eight isolates of independent origin and subjected to bisulphite treatment. This deaminates cytosine to uracil in single-stranded DNA but does not deaminate 5-methyl cytosine. PCR, cloning and sequencing revealed the methylation pattern of CpG doublets in the promoter region of the APRT- gene, whereas the active APRT gene had nonmethylated DNA. CHO strain K1, which has two copies of the APRT+ gene, could also be silenced by the same procedure but at a lower frequency. The availability of the 5-methyl dCTP-induced silencing, 5-aza-CR and a standard mutagen, ethyl methane sulphonate, makes it possible to follow concomitantly the inheritance of active, mutant or silenced gene copies. This analysis demonstrates "dual inheritance" at the APRT locus in CHO cells.

Adenine Phosphoribosyltransferase↗
PubMed1972

Inheritance of hair constrictions in mice.

The frequencies of multi-constricted hairs in the pelage is the same (75%) in the caudal mid-dorsum of C57BL/10 and CBA inbred mice, but there are more single-constricted hairs in C57BL mice (9.41%) than in CBA mice (0.13%). This structural feature is used as a basis for genetic analysis of the hair coat.-The frequency of single-constricted hairs (4.41%) in F(1) mice is intermediate between the frequencies observed in the CBA and C57BL parent strains. Data from the F(2) crosses and backcrosses to the respective parent strains indicate that the presence of numerous single-constricted hairs in the pelage is an inherited characteristic. The mode of inheritance is controlled primarily by a semi-dominant autosomal gene (single-constriction; Hct), without the involvement of maternal factors.

Animals↗
PubMed1975

Gene transfer in Caulobacter crescentus: polarized inheritance of genetic markers.

Recombination frequencies were determined for 15 independently isolated auxotrophs of C. crescentus crossed pairwise in all possible combinations. The results indicate that the mutants may be grouped into at least two types: "fertile" strains, which recombine with all other mutants at frequencies ranging from less than 10-6 to 3 times 10-2, and "nonfertile" strains which recombine with fertile strains at high frequencies and with other nonfertile strains at low or negligible frequencies. Several lines of evidence indicate a polarized inheritance of markers. Two of these are (1) the preferential inheritance of unselected markers from the nonfertile parent in fertile times nonfertile crosses, and (2) the consistent ordering of markers based on the frequency at which the mutants recombine with each of the three fertile strains. Although the evidence is not conclusive at this point, the results are most consistent with conjugation at the mechanism of gene transfer in these bacteria.

Cell Division↗
PubMed1992

Living arrangements of elderly Japanese and attitudes toward inheritance.

Using data from the 1988 Mainichi Newspaper/Nihon University National Family Survey, we analyzed the living arrangements and attitudes toward inheritance of Japanese aged 60 and over. Logit analysis indicates that living arrangements are influenced by gender, age, marital status, education, urban residence, and number of living children. Log-linear modeling of inheritance attitudes shows that living with married children, lower educational attainment, and living in a traditionally agricultural area are associated with favoring bequests to eldest sons, as opposed to bequests to all children equally or to whoever takes care of the elderly person. The results are consistent with modernization theory of gerontology and convergence theory of family sociology in that elderly persons with more "modern" characteristics are more likely to depart from prewar ideals of living with married children and preferring bequests to eldest sons only.

Aged↗
PubMed2002

Retinitis pigmentosa and allied diseases: numerous diseases, genes, and inheritance patterns.

Retinitis pigmentosa (RP) and allied diseases are heterogeneous clinically and genetically. Here we summarize the retinal cell types involved in these diseases, the large number of genes that cause them, and the variety of inheritance patterns that the affected families display. Special consideration is given to unusual inheritance patterns. The aggregate carrier frequency for recessive RP alleles may be as high as 10%.

Alleles↗
PubMed1995

Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNASer(UCN) gene.

We report on a new maternally-inherited syndrome characterized by a combination of sensorineural hearing loss, ataxia and myoclonus in a large kindred from Sicily. Hearing loss was the most widespread and sometimes the only symptom found in family members. Sequence analysis of the mitochondrial DNA regions encompassing the tRNA genes revealed the presence of a heteroplasmic insertion at nucleotide position 7472. The insertion adds a seventh cytosine to a six-cytosine run that is part of the mitochondrial tRNASer(UCN) gene. Conformational analysis showed that this mutation is likely to alter the structure of the T psi C loop in the tRNASer(UCN) clover leaf secondary structure. Moreover, the degree of heteroplasmy in blood and muscle was correlated with the clinical phenotype, and homoplasmic mutant hybrids showed decreased complex I activity, low oxygen consumption and high lactic acid output, indicating faulty oxidative phosphorylation. Finally, mutation was absent in 381 unrelated maternal lineages, suggesting specific segregation with the disease. We propose that the C7472 insertion-mutation is pathogenic, and etiologically related to hearing loss and other symptoms that define a novel maternally-inherited clinical entity.

Ataxia↗
PubMed1996

Crigler-Najjar syndrome type II is inherited both as a dominant and as a recessive trait.

Crigler-Najjar syndrome type II (CN-II) is caused by a severely reduced hepatic activity of bilirubin UDP-glucuronosyltransferase (UGT). Recently, by the analysis of the genetic background of CN-II patients, it has been clarified that the patients carry homozygous missense mutations or nonsense plus missense mutations on the gene for UGT, and CN-II was inherited as an autosomal recessive trait. We encountered a new case which had a nonsense mutation caused by a single nucleotide substitution on one allele. This indicates that CN-II is also inherited as a dominant trait as well as a recessive trait. Expression study in vitro strongly suggests that the disease in this case is caused by a dominant negative mutation by forming a heterologous subunit structure.

Amino Acid Sequence↗
PubMed1996

Survey of CAG/CTG repeats in human cDNAs representing new genes: candidates for inherited neurological disorders.

Expansion of polymorphic CAG and CTG repeats in transcripts is the cause of six inherited neurodegenerative or neuromuscular diseases and may be involved in several other genetic disorders of the central nervous system. To identify new candidate genes, we have undertaken a large-scale screening project for CAG and CTG repeats in human reference cDNAs. We screened 100 128 brain cDNAs by hybridization. We also scanned GenBank expressed sequence tags for the presence of long CAG/CTG repeats in the extremities of cDNAs from several human tissues. Of the selected clones, 286 were found to represent new genes, and 72 have thus far been shown to contain CAG/CTG repeats. Our data indicate that CAG/CTG repeated 10 or more times are more likely to be polymorphic, and that new 3'-directed cDNAs with such repeats are very rare (1/2862). Nine new cDNAs containing polymorphic (observed heterozygote frequency: 0.05-0.90) CAG/CTG repeats have been currently identified in cDNAs. All of the cDNAs have been assigned to chromosomes, and six of them could be mapped with YACs to 1q32-q41, 3p14, 4q28, 3p21 and 12q13.3, 13q13.1-q13.2, and 19q13.43. Three of these clones are highly polymorphic and represent the most likely candidate genes for inherited neurodegenerative diseases and, perhaps, neuropsychiatric disorders of multifactorial origin.

Brain↗
PubMed1997

Pathophysiological mechanisms of dominant and recessive KVLQT1 K+ channel mutations found in inherited cardiac arrhythmias.

The inherited long QT syndrome (LQTS), characterized by a prolonged QT interval in the electrocardiogram and cardiac arrhythmia, is caused by mutations in at least four different genes, three of which have been identified and encode cardiac ion channels. The most common form of LQTS is due to mutations in the potassium channel gene KVLQT1, but their effects on associated currents are still unknown. Different mutations in KVLQT1 cause the dominant Romano-Ward (RW) syndrome and the recessive Jervell and Lange-Nielsen (JLN) syndrome, which, in addition to cardiac abnormalities, includes congenital deafness. Co-expression of KvLQT1 with the IsK protein elicits slowly activating potassium currents resembling the cardiac Iks current. We now show that IsK not only changes the kinetics of KvLQT1 currents, but also its ion selectivity. Several mutations found in RW, including a novel mutation (D222N) in the putative channel pore, abolish channel activity and reduce the activity of wild-type KvLQT1 by a dominant-negative mechanism. By contrast, a JLN mutation truncating the carboxyterminus of the KvLQT1 channel protein abolishes channel function without having a dominant-negative effect. This fully explains the different patterns of inheritance. Further, we identified a novel splice variant of the KVLQT1 gene, but could not achieve functional expression of this nor of a previously described heart-specific isoform.

Amino Acid Sequence↗
PubMed1999

Allelic and locus heterogeneity in inherited venous malformations.

Venous malformations are low-flow vascular lesions consisting of disorganized thin-walled vascular channels. These can occur sporadically but also as an autosomal dominant condition termed venous malformations, cutaneous and mucosal (VMCM; OMIM 600195). In two large unrelated kindreds mapping to chromosome 9, the identical R849W missense mutation was identified in the first kinase domain of Tie2, an endothelial cell-specific receptor tyrosine kinase. We report here the identification of four new kindreds with inherited venous malformations. Unlike the initial two families described, these four families demonstrate allelic and locus heterogeneity. In one of these families, the R849W mutation co-segregates with the disease phenotype. Three other families with venous malformations lack this mutation. One of these families is linked to markers near TIE2 on chromosome 9. In this family, we identified a novel mutation within the first kinase domain of Tie2 resulting in a Y897S change. Results from COS-1 cell transfections using expression constructs containing either the R849W or the Y897S mutation suggest that the receptors containing either mutation show ligand-independent hyperphosphorylation. These results suggest a gain-of-function mechanism for development of venous malformations in these families. Of the two remaining families, one excludes linkage to the TIE2 locus, establishing the existence of at least one additional locus for dominantly inherited venous malformations.

Amino Acid Sequence↗