Estimating the effective number of breeders from heterozygote excess in progeny.
(1/1398)
The heterozygote-excess method is a recently published method for estimating the effective population size (Ne). It is based on the following principle: When the effective number of breeders (Neb) in a population is small, the allele frequencies will (by chance) be different in males and females, which causes an excess of heterozygotes in the progeny with respect to Hardy-Weinberg equilibrium expectations. We evaluate the accuracy and precision of the heterozygote-excess method using empirical and simulated data sets from polygamous, polygynous, and monogamous mating systems and by using realistic sample sizes of individuals (15-120) and loci (5-30) with varying levels of polymorphism. The method gave nearly unbiased estimates of Neb under all three mating systems. However, the confidence intervals on the point estimates of Neb were sufficiently small (and hence the heterozygote-excess method useful) only in polygamous and polygynous populations that were produced by <10 effective breeders, unless samples included > approximately 60 individuals and 20 multiallelic loci. (+info)
Mutations in the organic cation/carnitine transporter OCTN2 in primary carnitine deficiency.
(2/1398)
Primary carnitine deficiency is an autosomal recessive disorder of fatty acid oxidation caused by defective carnitine transport. This disease presents early in life with hypoketotic hypoglycemia or later in life with skeletal myopathy or cardiomyopathy. The gene for this condition maps to 5q31.2-32 and OCTN2, an organic cation/carnitine transporter, also maps to the same chromosomal region. Here we test the causative role of OCTN2 in primary carnitine deficiency by searching for mutations in this gene in affected patients. Fibroblasts from patients with primary carnitine deficiency lacked mediated carnitine transport. Transfection of patient's fibroblasts with the OCTN2 cDNA partially restored carnitine transport. Sequencing of the OCTN2 gene revealed different mutations in two unrelated patients. The first patient was homozygous (and both parents heterozygous) for a single base pair substitution converting the codon for Arg-282 to a STOP codon (R282X). The second patient was a compound heterozygote for a paternal 1-bp insertion producing a STOP codon (Y401X) and a maternal 1-bp deletion that produced a frameshift creating a subsequent STOP codon (458X). These mutations decreased the levels of mature OCTN2 mRNA and resulted in nonfunctional transporters, confirming that defects in the organic cation/carnitine transporter OCTN2 are responsible for primary carnitine deficiency. (+info)
Novel mutation of the P0 extracellular domain causes a Dejerine-Sottas syndrome.
(3/1398)
A patient is described with a Dejerine-Sottas syndrome caused by a novel heterozygous Cys(98)Tyr mutation in the extracellular domain of the major peripheral myelin protein zero (P0ex). Homotypical interactions between P0ex tetramers of apposed extracellular faces of the Schwann cell membrane play a crucial part in myelin compaction. The amino acid change disrupts a unique disulphide bond that stabilises the immunoglobulin-like structure of P0ex and it is predicted to cause severe dehypomyelination through dominant negative effects on the wild type protein. (+info)
Requirement for the c-Maf transcription factor in crystallin gene regulation and lens development.
(4/1398)
The vertebrate lens is a tissue composed of terminally differentiated fiber cells and anterior lens epithelial cells. The abundant, preferential expression of the soluble proteins called crystallins creates a transparent, refractive index gradient in the lens. Several transcription factors such as Pax6, Sox1, and L-Maf have been shown to regulate lens development. Here we show that mice lacking the transcription factor c-Maf are microphthalmic secondary to defective lens formation, specifically from the failure of posterior lens fiber elongation. The marked impairment of crystallin gene expression observed is likely explained by the ability of c-Maf to transactivate the crystallin gene promoter. Thus, c-Maf is required for the differentiation of the vertebrate lens. (+info)
Iron overload in porphyria cutanea tarda.
(5/1398)
BACKGROUND AND OBJECTIVE: Porphyria cutanea tarda (PCT) is a disorder of porphyrin metabolism associated with decreased activity of uroporphyrinogen decarboxylase (URO-D) in the liver. The relevance of iron in the pathogenesis of PCT is well established: iron overload is one of the factors that trigger the clinical manifestations of the disease and iron depletion remains the cornerstone of therapy for PCT. A role for genetic hemochromatosis in the pathogenesis of iron overload in PCT has been hypothesized in the past but only after the recent identification of the genetic defect causing hemochromatosis has the nature of this association been partially elucidated. This review will outline current concepts of the pathophysiology of iron overload in PCT as well as recent contributions to the molecular epidemiology of hemochromatosis defects in PCT. EVIDENCE AND INFORMATION SOURCES: The authors of the present review have a long-standing interest in the pathogenesis, etiology and epidemiology of iron overload syndromes. Evidence from journal articles covered by the Science Citation Index(R) and Medline(R) has been reviewed and collated with personal data and experience. STATE OF THE ART AND PERPECTIVES: Mild to moderate iron overload plays a key role in the pathogenesis of PCT. The recent identification of genetic mutations of the hemochromatosis gene (HFE) in the majority of patients with PCT confirms previous hypotheses on the association between PCT and hemochromatosis, allows a step forward in the understanding of the pathophysiology of the disturbance of iron metabolism in the liver of PCT patients, and provides an easily detectable genetic marker which could have a useful clinical application. Besides the epidemiological relevance of the association between PCT and hemochromatosis, however, it remains to be fully understood how iron overload, and in particular the cellular modifications of the iron status secondary to hemochromatosis mutations, affect the activity of URO-D, and how the altered iron metabolism interacts with the other two common triggers for PCT and etiological agents for the associated liver disease: alcohol and hepatitis viruses. The availability of a genetic marker for hemochromatosis will allow some of these issues to be addressed by studying aspects of porphyrins and iron metabolism in liver samples obtained from patients with PCT, liver disease of different etiology and different HFE genotypes, and by in vitro studies on genotyped cells and tissues. (+info)
The obese gene is expressed in lean littermates of the genetically obese mouse (C57BL/6J ob/ob).
(6/1398)
Some individuals of the mixed group of "lean" littermates (+/ob and +/+) of (C57BL/6J ob/ob) often suggest phenotypic characteristics of ob/ob animals. Therefore, it was of interest to determine whether expression of the ob gene had physiological significance in +/ob animals. Body weight (BW), fasting blood glucose (FBG), and body core temperature (Tr) were monitored between 62 and 364 days of age in +/+ and +/ob mice. Among females but not males, +/ob mice were heavier (P = 0.003) and FBG levels were greater (P = 0.04) than in +/+ animals. Comparison of Tr indicated differences suggesting falling Tr in +/ob but rising Tr in +/+ mice with age in males but not females. Multivariate analysis of variance yielded genotype effects for both males (P = 0.002) and females (P = 0.02). BW, FBG, and Tr alone were sufficient at the 75% level for genotypic characterization and separation of +/? animals as +/ob or +/+; clearly, expression of the ob gene in heterozygotes of the +/ob animal may make the mixed +/? group inappropriate as lean controls. (+info)
Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling.
(7/1398)
Problems with diagnosis and genetic counseling occur for patients with autosomal recessive proximal spinal muscular atrophy (SMA) who do not show the most common mutation: homozygous absence of at least exon 7 of the telomeric survival motor neuron gene (SMN1). Here we present molecular genetic data for 42 independent nondeleted SMA patients. A nonradioactive quantitative PCR test showed one SMN1 copy in 19 patients (45%). By sequencing cloned reverse-transcription (RT) PCR products or genomic fragments of SMN1, we identified nine different mutations in 18 of the 19 patients, six described for the first time: three missense mutations (Y272C, T274I, S262I), three frameshift mutations in exons 2a, 2b, and 4 (124insT, 241-242ins4, 591delA), one nonsense mutation in exon 1 (Q15X), one Alu-mediated deletion from intron 4 to intron 6, and one donor splice site mutation in intron 7 (c.922+6T-->G). The most frequent mutation, Y272C, was found in 6 (33%) of 18 patients. Each intragenic mutation found in at least two patients occurred on the same haplotype background, indicating founder mutations. Genotype-phenotype correlation allowed inference of the effect of each mutation on the function of the SMN1 protein and the role of the SMN2 copy number in modulating the SMA phenotype. In 14 of 23 SMA patients with two SMN1 copies, at least one intact SMN1 copy was sequenced, which excludes a 5q-SMA and suggests the existence of further gene(s) responsible for approximately 4%-5% of phenotypes indistinguishable from SMA. We determined the validity of the test, and we discuss its practical implications and limitations. (+info)
Radiation-induced G1 arrest is not defective in fibroblasts from Li-Fraumeni families without TP53 mutations.
(8/1398)
Radiation-induced G1 arrest was studied in four classes of early passage skin fibroblasts comprising 12 normals, 12 heterozygous (mut/wt) TP53 mutation-carriers, two homozygous (mut/-) TP53 mutation-carriers and 16 strains from nine Li-Fraumeni syndrome or Li-Fraumeni-like families in which no TP53 mutation has been found, despite sequencing of all exons, exon-intron boundaries, 3' and 5' untranslated regions and promoter regions. In an assay of p53 allelic expression in yeast, cDNAs from these non-mutation strains behaved as wild-type p53. Using two different assays, we found G1 arrest was reduced in heterozygous strains with mis-sense mutations and one truncation mutation, when compared to the range established for the normal cells. Heterozygous strains with mutations at splice sites behaved like normal cells, whilst homozygous (mut/-) strains showed either extremely reduced, or no, arrest. Strains from all nine non-mutation families gave responses within the normal range. Exceptions to the previously reported inverse correlation between G1 arrest and clonogenic radiation resistance were observed, indicating that these phenotypes are not strictly interdependent. (+info)