Biomedical subjects
P E Neumann
Publications and source records attributed to P E Neumann.
Detection of a R173W mutation in the porphobilinogen deaminase gene in the Nova Scotian "foreign Protestant" population with acute intermittent porphyria: a founder effect.
OBJECTIVES: Acute intermittent porphyria (AIP) is caused by mutations in the porphobilinogen deaminase (PBGD) gene that disrupt the function of the enzyme. Many mutations that lead to decreased PBGD activity have been described. An Arg to Trp substitution at codon 173 (CGG-->TGG in exon 10) and designated R173W, which leads to a CRIM-negative phenotype, has been reported in Swedish, Finnish, Scottish, and South African kindreds, and in a Nova Scotian proband with fatal AIP. In this work, we investigated the presence of this mutation in a Nova Scotian patient population presenting with AIP. DESIGN AND METHODS: Single-strand conformation polymorphism analysis and DNA sequencing by TA cloning and Sanger's dideoxy chain termination method, were used to confirm the maternal transmission of this mutation to the proband. The mutation also eliminates an Ncil (also Mspl) endonuclease restriction site, which allows for detection of the mutant allele by polymerase chain reaction amplification and restriction enzyme digestion. RESULTS: The family of the Nova Scotian proband and four other AIP kindreds showed the presence of the same mutation. These five families are descendants of German, Swiss, and French immigrants historically known as the "Foreign Protestants," who were recruited to Nova Scotia in the 1750s. CONCLUSION: In all these families, descent from one couple that settled in Nova Scotia in 1751 has been identified by genealogy research, consistent with a founder effect within this population. This is the first identified mutation in PBGD causing AIP that has been linked to a founder effect in descendants of an immigrant population to North America, and which could be traced to such a distant background, similar to the South African variegate porphyria mutation.
Genomic imprinting and audiogenic seizures in mice.
Audiogenic seizure (AGS) susceptibility in mice is a multifactorial behavioral disorder that involves severe generalized convulsions in response to loud, high-frequency sound. The inheritance of AGS susceptibility was examined in crosses between AGS-susceptible DBA/2J (D2) mice and epilepsy-prone (EP) mice. The EP mice were selected for high AGS susceptibility in a BALB/c-derived line. The AGS phenotype was similar in the EP and D2 mice at 30 days of age. The frequency of generalized clonic-tonic AGS was high in both the D2 and the EP mice (53 and 83%, respectively) but was low in the reciprocal EPD2F1 and D2EPF1 hybrids (14 and 19%, respectively). In the backcross to the EP parent, no significant associations were found between AGS susceptibility and microsatellite markers linked to Asp1 or Asp2, AGS genes located on Chromosomes 12 and 4, respectively. Significant associations were found for markers linked to Asp3, which is located in the proximal region of Chromosome 7. The influence of Asp3 on AGS susceptibility was seen in the EP x EPD2F1 backcross but not in the reciprocal EPD2F1 x EP backcross, suggesting that Asp3 expression is influenced by genomic imprinting. A model is proposed where genomic imprinting represses the maternal Asp3 allele, providing an influence largely from the paternal allele.
Mapping quantitative trait loci for open-field behavior in mice.
By performing a whole genome screen in an F2 intercross of two strains of mice (A/J and C57BL/6J), which differ markedly in their behavioral response to a brightly lit open field (O-F), we have mapped several quantitative trait loci (QTL) for this complex behavioral phenotype. QTL on chromosomes 1 and 10 were identified that affect both initial ambulation in the O-F (initial "response to novelty" ambulation) (lod of 7.1 and 8.8, respectively) and vertical rearings (lod of 4.5 and 8.5, respectively). For habituated O-F behavior, QTL were identified on chromosomes 3 and 10 for ambulation (lod of 4.1 and 14.7, respectively) and on chromosomes 1, 10, and 19 for vertical rearings (lod of 5.8, 6.0, and 4.7, respectively). The QTL on chromosome 1 (near D1Mit116; 101 cM) was specific for initial O-F ambulation behavior, whereas the QTL on chromosome 10 (near D10Mit237; 74 cM) affected both initial and habituated rearing behavior. Additional suggestive QTL (lod, > 2.8) were mapped to chromosomes 1, 8, 11, 15, and 19. The QTL on chromosomes 1, 10, and 19 individually explain from 3.2 to 12.7%. Collectively, the multiple independent QTL explain from 16.3 to 24.1% of the F2 population's phenotypic variance, depending on the trait. These identified QTL should prove useful for dissecting the genetic and behavioral dimensions of O-F behavior, fostering an understanding of individual differences.
Linkage of Niemann-Pick disease type D to the same region of human chromosome 18 as Niemann-Pick disease type C.
Niemann-Pick type II disease is a severe disorder characterized by accumulation of tissue cholesterol and sphingomyelin and by progressive degeneration of the nervous system. This disease has two clinically similar subtypes, type C (NPC) and type D (NPD). NPC is clinically variable and has been identified in many ethnic groups. NPD, on the other hand, has been reported only in descendants of an Acadian couple who lived in Nova Scotia in the early 18th century and has a more homogeneous expression resembling that of less severely affected NPC patients. Despite biochemical differences, it has not been established whether NPC and NPD are allelic variants of the same disease. We report here that NPD is tightly linked (recombination fraction .00; maximum LOD score 4.50) to a microsatellite marker, D18S480, from the centromeric region of chromosome 18q. Carstea et al. have reported that the NPC gene maps to this same site; therefore we suggest that NPC and NPD likely result from mutations in the same gene.
Limiting the Niemann-Pick type C critical region to a 1-cM interval.
OBJECTIVE: To refine the position of and isolate the gene responsible for Niemann-Pick Type II (NP Type II) disease, an autosomal, recessive neurodegenerative disorder usually affecting children. The underlying biochemical defect results in an impairment in transport of intracellular cholesterol. This disease has been classified into two subtypes, NPC and NPD. NPD and the major complementation group of NPC both map to chromosome 18q11-12; therefore, they are likely allelic variants. The NP Type II gene was previously localized between microsatellite markers D18S44 and D18S1108. DESIGN: Linkage analysis. SETTING: Pathology department of a university-associated hospital. PATIENTS: An NPC family, including proband, parents and sister. OUTCOME MEASURES: NP Type II disease phenotype and biochemical phenotype (cholesterol esterification). RESULTS: DNA from the individuals in the NPC family was genotyped at 12 microsatellite loci from the critical region. The deduced haplotypes identify a meiotic recombinant that has allowed the distal limit of the critical region to be moved from D18S1108 to D18S1101. CONCLUSION: The NP Type II gene lies proximal to the microsatellite marker D18S1101, within the 1-cM interval between D18S1101 and D18S1398. This represents approximately 1.1 mb on the physical map.
Altered sensory processing in the somatosensory cortex of the mouse mutant barrelless.
Mice homozygous for the barrelless (brl) mutation, mapped here to chromosome 11, lack barrel-shaped arrays of cell clusters termed "barrels" in the primary somatosensory cortex. Deoxyglucose uptake demonstrated that the topology of the cortical whisker representation is nevertheless preserved. Anterograde tracers revealed a lack of spatial segregation of thalamic afferents into individual barrel territories, and single-cell recordings demonstrated a lack of temporal discrimination of center from surround information. Thus, structural segregation of thalamic inputs is not essential to generate topological order in the somatosensory cortex, but it is required for discrete spatiotemporal relay of sensory information to the cortex.
Encyclopedia of the mouse genome V. Mouse chromosome 4.
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Genetic analysis of anxiety-related behaviors and responses to benzodiazepine-related drugs in AXB and BXA recombinant inbred mouse strains.
Recombinant inbred (RI) strains derived from the C57BL/6J and A/J mouse strains were used for behavioral studies designed to estimate the number and location of chromosomal loci responsible for anxiety-related behaviors and differential sensitivity to agonists and inverse agonists of the gamma-aminobutyric acidA (GABAA)/benzodiazepine receptor complex. The phenotypes of the parental inbred strains and of 28 RI strains were characterized for the number of transitions in the light<-->dark exploratory model, anxiolytic response to diazepam, vertical and ambulatory activities in an open field, and sensitivity to the convulsant properties of methyl-beta-carboline-3-carboxylate (beta-CCM). The strain distribution patterns and estimates of the minimal number of loci obtained for each trait suggest that multiple chromosomal loci contribute to differences in anxiety-related behavioral phenotypes and the behavioral responses to diazepam and beta-CCM between C57BL/6J and A/J mice. The best probabilities of linkage were found between the variables characterizing response to diazepam and loci on chromosomes 1 (Xmv-41) and 10 (D10Mit2) and between the sensitivity to the convulsant actions of beta-CCM and locus D15Mit5 on chromosome 15.
Multifactorial inheritance of neural tube defects: localization of the major gene and recognition of modifiers in ct mutant mice.
Neural tube defects (NTD) in humans have been considered to have a multifactorial aetiology, however the participating genes have not been identified. The curly-tail (ct) mutant mouse develops NTD that resemble the human malformations in location, pathology and associated abnormalities. Moreover, there appears to be multifactorial influence on the incidence of NTD in offspring of curly-tail mice. We now describe a linkage analysis that localizes the ct gene to distal chromosome 4 in mice. Further analysis using recombinant inbred strains demonstrates the presence of at least three modifier loci that influence the incidence of NTD. This study provides definitive evidence for multifactorial inheritance in a mouse model of human NTD.
Further evidence that a mouse chromosome 4 locus influences cerebellar folial pattern.
The cerebellar folial pattern of mice displays marked variation among inbred strains. Previous studies of progeny of crosses of C57BL/6 mice with DBA/2J and BALB/cByJ mice indicated a multifactorial mode of inheritance in both cases. The cross with DBA/2J led to the mapping, to Chromosome 4, of a locus (Cfp-1) that influences the frequency of the intraculminate fissure. Here we report that Cfp-1 influences the frequency of the declival sulcus, and appears to influence the frequency of the intraculminate and precentral fissures, in F2 hybrid offspring from crosses of C57BL/6J and BALB/cByJ mice.
Genetic analysis of cerebellar folial pattern in crosses of C57BL/6J and DBA/2J inbred mice.
Variation in the cerebellar folial pattern of mice is influenced by genetic elements [Inouye, M. and Oda, S., J. Comp. Neurol., 190 (1980) 357-362]. In crosses of C57BL/6J and DBA/2J inbred mice, the presence or absence of a specific fissure, the intraculminate fissure, is largely determined by a single genetic locus (Cfp-1), which is located on distal Chromosome 4 [Neumann et al., Brain Res., 524 (1990) 85-89]. In the present study, the mid-sagittal cerebellar folial pattern has been examined in crosses of C57BL/6J and DBA/2J mice and in BXD recombinant inbred strains. At least three loci, including Cfp-1, are involved in variation in vermian pattern formation. Genetic variation in thyroid hormone function may be involved in the inheritance of folial pattern. A locus (Cfp-2) that appears to be partially responsible for this negative genetic correlation in mice may be linked to Afp on Chromosome 5. This hypothesis was suggested by the negative correlation between neonatal serum T4 level and the number of folia in rats given neonatal injections of thyroxine or propylthiouracil [Lauder, J.M. et al., Brain Res., 76 (1974) 33-40].
Organization and promoter activity of the mouse syndecan-1 gene.
Syndecan-1, the prototype of a family of heparan sulfate-containing integral membrane proteoglycans, associates extracellularly with a variety of matrix molecules and growth factors and intracellularly with the actin cytoskeleton. Expressed constitutively on epithelia in mature tissues and in a developmentally regulated manner on epithelial and induced mesenchymal cells during embryogenesis, syndecan-1 appears to be involved in controlling the shape and organization of cells and tissues. To better understand the function and regulation of syndecan-1, we determined the structure of the mouse syndecan-1 gene (Synd-1). Synd-1 is approximately 19.5 kilobases in size and is organized into five exons that appear conserved in other family members. Exon 1 encodes the signal peptide; exon 2, the N-terminal glycosaminoglycan attachment region; exon 3, the bulk of the extracellular domain; exon 4, the protease-susceptible site; and exon 5, the transmembrane and cytoplasmic domains which are highly homologous between syndecan family members. Synd-1 has three transcriptional start sites, two polyadenylation sites, and is not alternatively spliced to produce its 2.6- and 3.4-kilobase mRNA species. Upstream sequences have promoter activity and contain TATA and CAAT boxes as well as a variety of other potential binding sites for transcription factors, including Sp1 (GC box), NF-kappa B, MyoD (E box), and Antennapedia. The structure of the promoter region suggests that control of Synd-1 expression is both constitutive and developmentally regulated. Because Synd-1 exons encode discrete functional domains of the syndecan-1 protein that are conserved throughout the syndecan family, all syndecan genes are likely derived from a common ancestor.
Encyclopedia of the mouse genome III. October 1993. Mouse chromosome 15.
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Genetic and behavioral tests of the McManus hypothesis relating response to selection for lateralization of handedness in mice to degree of heterozygosity.
McManus advanced a genetic hypothesis to explain differences of lateralization between HI and LO lines of mice selectively bred for degree of handedness. It states that lateralization is a function of heterozygosity. Specifically it predicts that (a) the HI line will be more heterozygous than the LO line and (b) populations with a greater average heterozygosity (AH) will be more strongly lateralized. Both genetic and behavioral predictions were tested here. Results using coat color and biochemical variants show that AH in the HI line is somewhat less (not greater) than that in the LO line. The handedness of HET control mice and HI by LO reciprocal hybrids, where AH is greater than that of the HI line, exhibits lessened (not greater) lateralization. Results reject the heterozygosity hypothesis. A model for the inheritance of human handedness that accounts for difficulty in detecting heritable differences in degree of asymmetry is presented.
Susceptibility of AKXD recombinant inbred mouse strains to lymphomas.
We analyzed the susceptibility of 10 AKXD recombinant inbred (RI) mouse strains to lymphomas. These strains were derived from crosses of AKR/J, a highly lymphomatous strain, and DBA/2J, a weakly lymphomatous strain. Of the 10 strains analyzed, nine showed a high incidence of lymphoma development. As with the other 13 AKXD strains analyzed previously (M. L. Mucenski, B. A. Taylor, N. A. Jenkins, and N. G. Copeland, Mol. Cell. Biol. 6:4236-4243, 1986), the mean age at onset of lymphomas and lymphoma types varied among the strains. Whereas some strains were susceptible to T-cell lymphomas, as was the AKR/J parent, other strains were susceptible to B-cell lymphomas or to a combination of T- and B-cell lymphomas. Somatic mink cell focus-forming proviruses appeared causally associated with T-cell lymphomas, whereas somatic ecotropic proviruses appeared causally associated with B-cell lymphomas. Mice with T-cell lymphomas died significantly earlier than mice with other lymphoma types (stem, pre-B, or B cell and myeloid). The numbers of effective loci influencing the mean age at onset of lymphomas, the presence or absence of mink cell focus-forming viruses in tumors, and the frequency of T-cell lymphomas were estimated to be 3.9, 1.8, and 2.7, respectively. Tests of association with marker loci already typed in the AKXD RI strains suggested that two loci, Rmcf and Pmv-25 (or a locus linked to Pmv-25), influence all three trait variables. Finally, D21S16h, a marker locus on distal chromosome 16, showed 50% probability of linkage to a locus that influences the mean age at onset of lymphomas. Additional studies in combination with classical genetic crosses should be helpful in confirming these linkages and in identifying other loci influencing tumor susceptibility in AKXD RI strains.
Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy.
Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, we propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative to Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being hemizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.