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PubMedDate not supplied

Phenotyping of CYP1A2 in Japanese population by analysis of caffeine urinary metabolites: absence of mutation prescribing the phenotype in the CYP1A2 gene.

Caffeine has been used as a metabolic probe to determine the relative levels of CYP1A2 activity in different individuals, since this compound is specifically 3-demethylated by CYP1A2. Urine specimen obtained at a 4-5-h interval after caffeine ingestion from 205 Japanese were analyzed using the [1,7-dimethyluric acid + 1,7-dimethylxanthine]/caffeine (1,3,7-trimethylxanthine) ratio, which better correlated with the rate constant for caffeine 3-demethylation than other ratios. The probit analyses of nonsmokers (n = 147) and smokers (n = 58) suggested that the CYP1A2 activity was not normally distributed and appeared bimodal. The breakpoints were at 5.0 and 6.0 of (1,7-dimethyluric acid + 1,7-dimethylxanthine)/1,3,7-trimethylxanthine ratio in nonsmokers and smokers, respectively. The bimodal probit plot suggested the existence of poor and extensive phenotypes. The percentage of individuals with the poor phenotype in Japanese was 14.1%. Induction of CYP1A2 by cigarette smoking was confirmed by the higher molar ratio observed in smokers (P < 0.0001). The CYP1A2 ratio was also higher in males than in females (P = 0.04). A reproducibility study of 12 subjects in an 11 month interval period showed that intraindividual variability did not alter this CYP1A2 phenotypic classification. Family study in eight pedigrees suggested that the poor phenotype of CYP1A2 inherited as an autosomal recessive trait. The sequences of CYP1A2 gene from poor and extensive metabolizers were analyzed. Although no differences of nucleotide sequence were observed in exons, exon-intron junctions and 5'-flanking regions (up to -2.6 kilobases) of CYP1A2 gene between each phenotype, there were some sequences which differed from the previous reported data. This is the first report in which the CYP1A2 phenotype and a genetic polymorphism in the CYP1A2 gene were comparably investigated.

Adolescent↗

PubMed1997

Genetic and phenotypic analysis of a large (122-member) protein S-deficient kindred provides an explanation for the familial coexistence of type I and type III plasma phenotypes.

Protein S deficiency is a known risk factor for thrombosis. The coexistence of phenotypic type I (reduction in total and free antigen) and type III (reduction in free antigen only) protein S deficiencies in 14 of 18 families was recently reported. We investigated the cause of this phenotypic variation in the largest of these families (122 family members, including 44 affected individuals) using both molecular genetic and phenotypic analysis. We have identified a sole causative mutation (Gly295Val) in three family members representative of the variable phenotype. Complete cosegregation of the mutation with reduced free protein S antigen levels was found, regardless of the total antigen level. Analysis of phenotypic data showed high correlations between total protein S antigen and age in both normal and protein S-deficient family members, irrespective of gender. Free protein S antigen levels were not influenced by age, a finding explained by an association between beta-chain containing C4b-binding protein (C4bBP-beta+) antigen levels and age. We propose that the identified Gly295Val mutation causes quantitative, or type I, protein S deficiency, and that as age increases the total protein S antigen level normalizes with respect to the reference plasma pool, giving rise to a type III protein S-deficient phenotype.

Adolescent↗

PubMed2000

Clustering of mutations associated with mild Marfan-like phenotypes in the 3' region of FBN1 suggests a potential genotype-phenotype correlation.

Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, a dominantly inherited disorder of connective tissue that primarily involves the cardiovascular, ocular, and skeletal systems. There is a remarkable degree of variability both within and between families with Marfan syndrome, and FBN1 mutations have also been found in a range of other related connective tissue disorders collectively termed type-1 fibrillinopathies. FBN1 mutations have been found in almost all of the 65 exons of the FBN1 gene and for the most part have been unique to one affected patient or family. Aside from the "hot spots" for the neonatal Marfan syndrome in exons 24-27 and 31-32, genotype-phenotype correlations have been slow to emerge. Here we present the results of temperature-gradient gel electrophoresis analysis of FBN1 exons 59-65. Six mutations were identified, only one of which had been previously reported. Two of the six mutations were found in patients with mild phenotypes. Taken together with other published reports, our results suggest that a sizable subset (ca. 40%) of mutations in this region is associated with mild phenotypes characterized by the lack of significant aortic pathology, compared with about 7% in the rest of the gene. In two cases, mutations affecting analogous positions within one of the 43 cbEGF modules of FBN1 are associated with mild phenotypes when found in one of the 6 C-terminal modules (encoded by exons 59-63), but are associated with classic or severe phenotypes when found in cbEGF modules elsewhere in the gene.

Adolescent↗

PubMed1981

Reversibility of the transformed and neoplastic phenotype. I. Progressive reversion of the phenotype of X-ray-transformed C3H/10T1/2 cells under prolonged treatment with interferon.

X-ray transformed mouse C3H/10T1/2 cells were cultivated and passaged in the continuous presence of partially purified mouse interferon. This prolonged interferon treatment resulted in a stepwise progressive reversion of the transformed phenotype to the non-transformed phenotype. Thus interferon-treated cells displayed an epithelioid morphology, grew to a lower cell density, and were no longer tumorigenic. Reversion to the non-transformed phenotype was, however, stable only as long as interferon was continuously present in the culture medium. When interferon was removed, the cells "back reverted" to the transformed phenotype. Our results suggest that interferon induced a reversion of the transformed phenotype in the entire cell population rather than a selection of an interferon resistant cell population. C-type viral particles and significant levels of reverse transcriptase were present in transformed cells, but neither present in the parental 10T1/2 cells nor in interferon-treated cells. When interferon was removed form the culture medium, viral particles and reverse transcriptase activity were again detected. It is possible, therefore, that interferon induces reversion through its antiviral activity, or that it induces reversion by its effects on cell function and structure, independently of any antiviral effect. Inhibition of cell multiplication per se does no appear to be sufficient to induce reversion, since cycloheximide inhibited cell multiplication; however, even after ten passages, it did not affect tumorigenicity. Our results suggest the possibility that interferon may act in vivo not only by inhibiting tumor cell multiplication but also by inducing a reversion. Patients with some tumors may therefore benefit from long-term interferon treatment.

Animals↗

PubMed1997

Deletions in Xq26.3-q27.3 including FMR1 result in a severe phenotype in a male and variable phenotypes in females depending upon the X inactivation pattern.

High resolution cytogenetics, microsatellite marker analyses, and fluorescence in situ hybridization were used to define Xq deletions encompassing the fragile X gene, FMR1, detected in individuals from two unrelated families. In Family 1, a 19-year-old male had facial features consistent with fragile X syndrome; however, his profound mental and growth retardation, small testes, and lover limb skeletal defects and contractures demonstrated a more severe phenotype, suggestive of a contiguous gene syndrome. A cytogenetic deletion including Xq26.3-q27.3 was observed in the proband, his phenotypically normal mother, and his learning-disabled non-dysmorphic sister. Methylation analyses at the FMR1 and androgen receptor loci indicated that the deleted X was inactive in > 95% of his mother's white blood cells and 80-85% of the sister's leukocytes. The proximal breakpoint for the deletion was approximately 10 Mb centromeric to FMR1, and the distal breakpoint mapped 1 Mb distal to FMR1. This deletion, encompassing approximately 13 Mb of DNA, is the largest deletion including FMR1 reported to date. In the second family, a slightly smaller deletion was detected. A female with moderate to severe mental retardation, seizures, and hypothyroidism, had a de novo cytogenetic deletion extending from Xq26.3 to q27.3, which removed approximately 12 Mb of DNA around the FMR1 gene. Cytogenetic, and molecular data revealed that approximately 50% of her white blood cells contained an active deleted X. These findings indicate that males with deletions including Xq26.3-q27.3 may exhibit a more severe phenotype than typical fragile X males, and females with similar deletions may have an abnormal phenotype if the deleted X remains active in a significant proportion of the cells. Thus, important genes for intellectual and neurological development, in addition to FMR1, may reside in Xq26.3-q27.3. One candidate gene in this region, SOX3, is thought to be involved in neuronal development and its loss may partly explain the more severe phenotypes of our patients.

Adult↗

PubMed2005

Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty-five Czech and Slovak patients. A multi-approach study.

A multi-approach study in a series of 25 Czech and Slovak patients with acid sphingomyelinase deficiency revealed a broad phenotypic variability within Niemann-Pick disease types A and B. The clinical manifestation of only 9 patients fulfilled the historical classification: 5 with the rapidly progressive neurovisceral infantile type A and 4 with a slowly progressive visceral type B. Sixteen patients (64%) represented a hitherto scarcely documented 'intermediate type' (IT). Twelve patients showed a protracted neurovisceral course with overt or mild neurological symptoms, three a rapidly progressing fatal visceral affection with rudimentary neurological lesion. One patient died early from a severe visceral disease. The genotype in our patients was represented by 4 frameshift and 14 missense mutations. Six were novel (G166R, R228H, A241V, D251E, D278A, A595fsX601). The Q292K mutation (homoallelic, heteroallelic) was strongly associated with a protracted neurovisceral phenotype (10 of 12 cases). The sphingomyelin loading test in living fibroblasts resulted in total degradation from less than 2% in classical type A to 70-80% in classical type B. In the IT group it ranged from 5% to 49% in a 24 h chase. The liver storage showed three patterns: diffuse, zonal (centrolobular), and discrete submicroscopic. Our series showed a notable variability in both the neurological and visceral lesions as well as in their proportionality and synchrony, and demonstrates a continuum between the historical 'A' and 'B' phenotypes of ASM deficiency. This points to a broad phenotypic potential of ASM deficiency, suggesting the existence of still unknown factors independently controlling the storage level in the visceral and neuronal compartments. This report highlights the important position of the IT in the ASM deficiency phenotype classification. We define IT as a cluster of variants combining clinical features of both the classical types. The protracted neuronopathic variant with overt, borderline or subclinical neurology prevails and is important in view of future enzyme replacement therapy. It appears more common in central Europe. The visceral, rapidly progressing early fatal type has been recognized rarely so far.

Adolescent↗

PubMed1986

Modulation of the rabbit chondrocyte phenotype by retinoic acid terminates type II collagen synthesis without inducing type I collagen: the modulated phenotype differs from that produced by subculture.

The differentiated phenotype of rabbit articular chondrocytes can be characterized by the synthesis of high levels of cartilage specific proteoglycan and collagen (type II). Treatment of these cells in primary monolayer culture for periods of up to 18 days with 0.03 to 3.0 micrograms/ml retinoic acid (RA) resulted in suppression of colony formation, altered morphology, and decreased (eightfold) proteoglycan and collagen synthesis. With the exception of collagen synthesis, these changes were complete with all doses after 4 days of treatment. Collagen synthesis declined more slowly; it was dose dependent after 4 days and maximally inhibited by all doses by 9 days. Detailed analysis of the collagen phenotype was performed using SDS-PAGE of intact chains and 2-D CNBr peptide analysis. RA caused cessation of type II synthesis, and transient stimulation of type III and type I trimer collagen synthesis, without induction of type I collagen. Essentially identical results were obtained with retinol. The resultant collagen phenotype differed significantly from the type I-containing phenotype induced by subculture. Thus, suppression of this differentiated program did not elicit a common modulated phenotype. The results are discussed in the context of direct and indirect mechanisms of RA-dependent modulation of chondrocyte gene expression.

Animals↗

PubMed1998

A comparison of power to detect a QTL in sib-pair data using multivariate phenotypes, mean phenotypes, and factor scores.

The power to detect a quantitative trait locus (QTL) in sib-pair data is investigated. We assume that we have at our disposal 3 or 4 related phenotypic measures in a sample of sib-pairs. Individual differences in these phenotypes are due to a common QTL and specific (i.e., unique to each phenotype) nonshared environmental and specific polygenic additive effects. In addition, models are considered that include common nonshared environmental effects and/or common polygenic additive effects. We calculate the power to detect the QTL in a genetic covariance structure analysis of the multivariate data, of the mean phenotypic data, and of factor scores. The use of factor scores is shown to be universally more powerful than the use of multivariate or mean phenotypic data. We also investigate the effect of using a single sample of sib-pairs to both calculate the factor score regression matrix and to carry out the QTL analysis. The use of a single sample to both these ends results in a loss of power compared to the theoretical, expected power. The gain in power attributable to the use of factor scores, however, outweighs this observed loss in power. The advantages of using factor scores in selecting sib-pairs are discussed.

Chi-Square Distribution↗

PubMed1984

Complement phenotypes in glomerulonephritis: increased frequency of homozygous null C4 phenotypes in IgA nephropathy and Henoch-Schönlein purpura.

Polymorphism of three complement genes (C4A, C4B, and BF) located within the major histocompatibility complex was studied in 48 biopsy-proven IgA nephropathy patients and nineteen patients with Henoch-Schönlein purpura (HSP). Polymorphism was determined by immunoelectrophoretic techniques and functional activity using an overlay of sheep cells in agarose and C4 deficient sera. The subjects were divided into four large groups according to the presence or absence of a C4 null allele (a gene producing no identifiable gene product): group 1 (no null variants), group 2 (one C4A null variant), group 3 (one C4B null variant), and group 4 (two null variants at either the C4A or C4B locus, that is, homozygous null). Patients had a significantly increased frequency of group 4 phenotypes (homozygous null): (12 of 67 patients, 17.8%) as compared to controls (4 of 102 patients, 3.9%, P = 0.0031). Both IgA (P = 0.045) and HSP patients (P = 0.003) had a greater frequency of a C4 homozygous null phenotype. The serum C4 concentration was higher in patients than in controls (740 mg/ml and 576 micrograms/ml, respectively, P = less than 0.001) whether evaluated together or by C4 phenotypic group. The association between the presence of IgA nephropathy or HSP with a homozygous C4 null phenotype is of unknown significance but suggests a predisposition to development of HSP or IgA nephropathy for individuals with the C4 homozygous null phenotype.

Chromosome Mapping↗

PubMed2003

From phenomenon to phenotype and from phenotype to gene: forward genetics and the problem of sepsis.

Genetic tools (especially classical tools) have enlightened our understanding of biology as no other approach could. Mendel, Morgan, Bridges, and their heirs began with phenotypic traits and ended with genes. At first, the chemical identity of genes was not known, and even after years of methodologic refinement, more years of effort were needed to find the gene and the mutational difference that caused a particular phenotype. Chemistry has now outraced phenotypic analysis; all the genes are suddenly known, but most of their functions are not. The greatest challenge confronting all fields in biology is to establish correspondence between genes and discrete biologic functions. Sepsis is a devastating problem that has eluded a solution, despite the introduction of highly effective antimicrobial agents. Sepsis is an orchestrated process, understood in broad outline, but not in all details. Which genes are involved in the pathogenesis of sepsis? As in the golden age of genetics, the answer requires the solution of phenotypic puzzles, which, in turn, requires the creation of phenotypes.

Animals↗

PubMed2007

Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas.

CONTEXT: Mutations of the gene encoding succinate dehydrogenase subunit B (SDHB) predispose to malignant paraganglioma (PGL). Recognition of the SDHB phenotype in apparently sporadic PGL directs appropriate treatment and family screening. OBJECTIVE: The objective of the study was to assess mutation-specific clinical and biochemical characteristics of SDHB-related PGL. DESIGN: The study design was retrospective descriptive. PATIENTS: PATIENTS included 29 patients (16 males) with SDHB-related abdominal or thoracic PGL. INTERVENTION: There was no intervention. MAIN OUTCOME MEASURES: Clinical presentations, plasma and urine concentrations of catecholamines and O-methylated metabolites, and genotype-phenotype correlations were measured. RESULTS: Mean +/- sd age at diagnosis was 33.7 +/- 15.7 yr. Tumor-related pain was among the presenting symptoms in 54% of patients and was the sole symptom in 14%. Seventy-six percent had hypertension, and 90% lacked a family history of PGL. All primary tumors but one originated from extraadrenal locations. Mean +/- sd tumor size was 7.8 +/- 3.7 cm. In this referral-based study, 28% presented with metastatic disease and all but one eventually developed metastases after 2.7 +/- 4.1 yr. Ten percent had additional head and neck PGLs. The biochemical phenotype was consistent with hypersecretion of both norepinephrine and dopamine in 46%, norepinephrine only in 41%, and dopamine only in 3%. Ten percent had normal catecholamine (metabolite) levels, consistent with biochemically silent PGL. No obvious genotype-phenotype correlations were identified. CONCLUSIONS: SDHB-related PGL often presents as apparently sporadic PGL with symptoms related to tumor mass effect rather than to catecholamine excess. The predominant biochemical phenotype consists of hypersecretion of norepinephrine and/or dopamine, whereas 10% of tumors are biochemically silent. The clinical expression of these tumors cannot be predicted by the genotype.

Adolescent↗

PubMed1984

Thymic lymphocytes. II. Phenotypic modifications of thymocytes after concanavalin A stimulation in the presence of interleukin 2: early modifications of Lyt 1+2+ subset and later proliferation of cells with more mature phenotypes.

Cortical thymocytes are devoid of any immune function, as tested by presently available techniques. The ability of this subpopulation to respond to mitogens or antigens in the presence of interleukin 2 (IL-2) produced by activated mature T lymphocytes has been claimed but is still questioned. In an attempt to study the participation of the different thymocyte subsets and especially that of the cortical type, phenotypic modifications were examined during concanavalin A activation in the presence of IL-2. An immunofluorescent double labeling technique with anti-Lyt 1 and anti-Lyt 2 antibodies was used which led to the determination of four different phenotypes: Lyt 1+2+, Lyt 1+2-, Lyt 1-2+, and Lyt 1-2-. Careful analysis of cell viability in culture and expression of the results in absolute numbers of living cells per culture allowed us to follow modifications of small cellular subsets. Cultures of total thymocytes and PNA-agglutinated (enriched in Lyt 1+2+ cells) and non-PNA-agglutinated cells (enriched in Lyt 1+2-, Lyt 1-2+, and Lyt 1-2- cells) were studied. It was shown that thymocyte activation began by early phenotypic modifications which took place within the first 2 hr of culture but only when Con A plus IL-2 were used. These modifications imply the reduction of the Lyt 1+2+ pool and a compensatory enhancement of Lyt 1-2+ and Lyt 1-2- cells, without modification of the total cell number or [3H]thymidine incorporation. These early phenotypic changes are interpreted as the modulation of antigens on the surface of Lyt 1+2+ cells. The second phase of thymocyte activation implies cell death (essentially Lyt 1+2+ cells) and cell proliferation. The cells which specifically proliferate in the presence of Con A and IL-2 are Lyt 1+2- and Lyt 1-2+, the latter always being present in greater number. Cell survival and absolute number of Lyt 1+2- and Lyt 1-2+ cells in the activated PNA- -enriched population are always higher than in total thymocyte and PNA+ cells cultures. Thus, if Lyt 1+2+ cortical thymocytes do not proliferate by themselves, they seem to intervene by providing Lyt 1-2+ cells which proliferate secondarily.

Animals↗

PubMed1992

Studies on apolipoprotein(a) phenotypes. Part 1. Phenotype frequencies in a healthy Japanese population.

The frequency distribution for serum lipoprotein(a) (Lp(a)) concentrations in healthy Japanese was highly skewed, with a mean +/- S.D. of 14.6 +/- 13.6 mg/dl and a median of 11.0 mg/dl. The present study provides the first evidence on the frequencies of Lp(a) phenotypes and alleles in healthy Japanese subjects. There was a strong inverse relationship between the apparent molecular weights of apo(a) isoforms and plasma Lp(a) concentrations, as reported previously. However, because of the considerable overlap between the Lp(a) concentrations of the different phenotypes, it was impossible to predict Lp(a) concentration from Lp(a) phenotypes, or vice versa. The present results suggest that the distribution of Lp(a) concentrations, mean and median values and Lp(a) phenotype and allele frequencies in healthy Japanese are not significantly different from the results for Europeans, whereas they are significantly different from other Asian populations, i.e. Chinese, Indians and Malaysians.

Adolescent↗

PubMed2005

Dimensional phenotypic analysis and functional categorisation of mutations reveal novel genotype-phenotype associations in Rett syndrome.

We aimed to improve the understanding of genotype-phenotype correlations in Rett syndrome (RS) by adopting a novel approach to categorising phenotypic dimensions - separating typicality of presentation, outcome severity and age of onset - and by classifying MECP2 mutations strictly by predicted functional attributes. MECP2 mutation screening results were available on 190 patients with a clinical diagnosis of RS (140 cases with classic RS, 50 with atypical RS). 135 cases had identified mutations. Of the 140 patients, 116 with classic RS (82.9%) had an identified mutation compared with 19 of 50 patients (38%) with an atypical presentation. Cases with early onset of regression and seizures, and those with clinical features that might indicate alternative aetiologies, were less likely to have mutations. Individuals with late truncating mutations had a less typical presentation than cases with missense and early truncating mutations, presumably reflecting greater residual function of MECP2 protein. Individuals with early truncating mutations had a more severe outcome than cases with missense and late truncating mutations. These findings held when restricting the analysis to cases over 15 years of age and classic cases only. Previous findings of variation in severity among the common mutations were confirmed. The approach to phenotypic and genotypic classification adopted here allowed us to identify genotype-phenotype associations in RS that may aid our understanding of pathogenesis and also contribute to clinical knowledge on the impact of different types of mutations.

Adolescent↗

PubMed2003

Phenotypic and genotypic relationship between Campylobacter spp isolated from humans and chickens in Northern Ireland--a comparison of three phenotyping and two genotyping schemes.

Human campylobacteriosis is currently the most common cause of acute bacterial gastroenteritis on the island of Ireland, accounting for over 3,000 laboratory reports per year, where circa 2,000 reports originate from the Republic of Ireland and circa 1,000 reports from Northern Ireland. Elsewhere, consumption of contaminated poultry has been associated with the zoonotic transmission of disease, therefore it was the aim of this study to examine the phenotypic and genotypic relatedness of campylobacters isolated from chickens and humans locally. Sixty isolates were subtyped using phenotyping techniques (biotyping, phage-typing), as well as genotyping techniques (multilocus enzyme electrophoresis (MEE), ribotyping) and the data compared. The frequency of shared phenotypes and genotypes between poultry and humans varied depending on the typing technique employed ranging from 98.2% of human isolates sharing a similar resistotyping (MAST) disc type with poultry strains to 20% similarity with MEE typing. Overall, this small study is the first report on phenotypic and genotypic relatedness between human and poultry campylobacters in Northern Ireland, isolated under controlled conditions. The study demonstrated an association between chicken and human sub-species types, taken from a relatively contained epidemiological environment. Further work is required with larger numbers of isolates coupled with typing schemes, which are able to reliably cluster strains from chicken and humans, which share high degrees of clonality, before local poultry can be conclusively proven to be a significant source of human campylobacteriosis.

Animals↗

PubMed2002

Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome.

BACKGROUND: Cardiovascular anomalies are among the most common features of Alagille syndrome (AGS). Mutations of JAG1 are found in most individuals with AGS. This study was undertaken to determine the spectrum of cardiovascular phenotypes associated with a JAG1 mutation and/or AGS, investigate potential genotype-phenotype correlations, and begin to correlate clinical outcome with genetic pathogenesis. METHODS AND RESULTS: We reviewed the records of 200 individuals with a JAG1 mutation or AGS. A total of 187 (94%) subjects had evidence of cardiovascular involvement. Cardiovascular anomalies were identified by imaging in 150 subjects (75%), and 37 (19%) had a peripheral pulmonary stenosis murmur with either a normal echocardiogram or no imaging study. Of the 150 subjects with anomalies confirmed by imaging, right-sided anomalies were present in 123 and left-sided anomalies in 22, with both in 12. Seventeen subjects had other anomalies. The most common abnormality was stenosis/hypoplasia of the branch pulmonary arteries (PAs), which was documented by imaging (n=111) or inferred from a peripheral pulmonary stenosis murmur (n=41) in 76% of subjects. Tetralogy of Fallot was present in 23 subjects and was accompanied by pulmonary atresia in 8. Branch PA phenotype differed between individuals with and without a JAG1 mutation. Among subjects with a JAG1 mutation, there was no correlation between the type or location of mutation and the frequency or type of cardiovascular anomaly. CONCLUSIONS: More than 90% of individuals with a JAG1 mutation or AGS have cardiovascular anomalies, with branch PA stenosis the most common abnormality. Cardiovascular phenotype does not correlate with the type or location of JAG1 mutation.

Alagille Syndrome↗

PubMed2004

The Mammalian Phenotype Ontology as a tool for annotating, analyzing and comparing phenotypic information.

The Mammalian Phenotype (MP) Ontology enables robust annotation of mammalian phenotypes in the context of mutations, quantitative trait loci and strains that are used as models of human biology and disease. The MP Ontology supports different levels and richness of phenotypic knowledge and flexible annotations to individual genotypes. It continues to develop dynamically via collaborative input from research groups, mutagenesis consortia, and biological domain experts. The MP Ontology is currently used by the Mouse Genome Database and Rat Genome Database to represent phenotypic data.

Animals↗

PubMed2002

Fabry disease: twenty novel alpha-galactosidase A mutations and genotype-phenotype correlations in classical and variant phenotypes.

BACKGROUND: Fabry disease (OMIM 301500) is an X-linked inborn error of glycosphingolipid metabolism resulting from mutations in the alpha-galactosidase A (alpha-Gal A) gene. The disease is phenotypically heterogeneous with classic and variant phenotypes. To assess the molecular heterogeneity, define genotype/phenotype correlations, and for precise carrier identification, the nature of the molecular lesions in the alpha-Gal A gene was determined in 40 unrelated families with Fabry disease. MATERIALS AND METHODS: Genomic DNA was isolated from affected males or obligate carrier females and the entire alpha-Gal A coding region and flanking sequences were amplified by PCR and analyzed by automated sequencing. Haplotype analyses were performed with polymorphisms within and flanking the alpha-Gal A gene. RESULTS: Twenty new mutations were identified (G43R, R49G, M72I, G138E, W236X, L243F, W245X, S247C, D266E, W287C, S297C, N355K, E358G, P409S, g1237del15, g10274insG, g10679insG, g10702delA, g11018insA, g11185-delT), each in a single family. In the remaining 20 Fabry families, 18 previously reported mutations were detected (R49P, D92N, C94Y, R112C [two families], F113S, W162X, G183D, R220X, R227X, R227Q, Q250X, R301X, R301Q, G328R, R342Q, E358K, P409A, g10208delAA [two families]). Haplotype analyses indicated that the families with the R112C or g10208delAA mutations were not related. The proband with the D266E lesion had a severe classic phenotype, having developed renal failure at 15 years. In contrast, the patient with the S247C mutation had a variant phenotype, lacking the classic manifestations and having mild renal involvement at 64 years. CONCLUSIONS: These results further define the heterogeneity of alpha-Gal A mutations causing Fabry disease, permit precise heterozygote detection and prenatal diagnosis in these families, and provide additional genotype/phenotype correlations in this lysosomal storage disease.

Fabry Disease↗