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PubMed2005

Genotype-phenotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease.

INTRODUCTION: The incidence of early-onset CD in Scotland is among the highest worldwide. Three single nucleotide polymorphisms (SNPs) R702W, G908R and Leu1007finsC in the NOD2/CARD15 gene predispose to adult CD. We investigated the contribution of these variants to disease susceptibility and phenotype in the Scottish early-onset IBD population. PATIENTS AND METHODS: 906 individuals including 247 Scottish IBD patients aged <16 years at diagnosis, 414 parents and 245 controls were genotyped. Transmission disequilibrium testing (TDT), case-control analysis and detailed genotype-phenotype analysis were performed. RESULTS: The Leu1007finsC variant was associated with susceptibility to CD by case-control (4.2% versus. 1.4%, P = 0.01) and TDT analysis (P = 0.006). The Population Attributable Risk (PAR) for the 3 NOD2/CARD15 mutations was 7.9%. Carriage of NOD2/CARD15 variants was associated with, at diagnosis: decreased albumin (31.0% versus. 9.0%, P = 0.001) and raised CRP (25% versus. 9.5%, P = 0.04) and at follow up: need for surgery (39.5% versus. 12.8%, P = 0.0002) jejunal involvement (50% versus. 18.4%, P = 0.01) jejunal and ileal involvement (50% versus. 10.7%, P = 0.009), raised CRP (57.1% and 12.8%, P = 0.0009), lower weight/height centile (75.0% versus. 20.2%, P = 0.03, 50.0% versus. 16.0%, P = 0.001 respectively) and stricturing disease (45.5% versus. 19.4%, P < 0.05). Multifactorial analysis demonstrated carriage was associated with need for surgery (P = 0.004, OR 4.9 [1.5-14.7]). CONCLUSIONS: These NOD2/CARD 15 variants in the Scottish early onset CD population have a definite, albeit relatively small contribution to CD susceptibility (PAR 7.9%) but a major impact on phenotype. In particular NOD2/CARD15 variants are strongly associated with several markers of disease severity in pediatric CD, notably need for surgery.

Adolescent↗
PubMed1981

Phenotypic and quantitative relationship of red cell acid phosphatase with haemoglobin, haptoglobin, and G6PD phenotypes.

The phenotypic and quantitative relationship of red cell acid phosphatase with haemoglobin, haptoglobin, and G6PD phenotypes was investigated in three populations in the Sudan and one population in Nilgiris, India. No significant consistent association of red cell acid phosphatase phenotypes was observed with these polymorphisms. However, there was a lack of acid phosphatase AB in G6PD deficient subjects from Nilgiris. The relative quantitative expression of red cell acid phosphatase genes PA, PB, and PC was 1.0, 1.2, and 1.3, respectively. The red cell acid phosphatase activity was higher (15%) in the presence of raised haemoglobin A2 and in sickle cell anaemia (21%). Those with Hp2 had 18% higher level of acid phosphatase than those with Hp1. G6PD deficient subjects had a lower level of acid phosphatase activity (20%) than those with normal G6PD activity.

Acid Phosphatase↗
PubMed2001

Phenotypic variations of orpk mutation and chromosomal localization of modifiers influencing kidney phenotype.

The Oak Ridge polycystic kidney (orpk) mutant mouse model resulted from a transgene insertion into the Tg737 gene and exhibits a pleiotropic syndrome with lesions in the kidney, liver, and pancreas. We found marked differences in the phenotypic expression of the orpk mutation when bred on different genetic backgrounds. In the FVB/N background, the phenotype is very severe for kidney, pancreas, and liver lesions. To evaluate better how genetic background might influence the expressivity of the orpk phenotype, we bred the transgene into the C3HeB/FeJLe (C3H) genetic background. We performed a genome-wide scan using backcross and intercross populations with more than 150 markers to map the chromosomal location of the modifier genes that differ in the FVB/N and C3H genetic backgrounds that affect the severity of kidney disease in the orpk mouse. Low-resolution interval mapping was performed using the Map Manager QTb program, with the interval explaining a significant portion of the variance being the distal end of chromosome 4.

Animals↗
PubMed2005

The phenotypic plasticity of myeloma plasma cells as expressed by dedifferentiation into an immature, resilient, and apoptosis-resistant phenotype.

PURPOSE: We previously showed the ability of osteoclasts to support myeloma plasma cell survival and proliferation in vivo and ex vivo. The aim of the current study was to investigate osteoclast-induced phenotypic changes associated with long-term survival of myeloma cells in coculture. EXPERIMENTAL DESIGN: CD138-selected myeloma plasma cells from 16 patients were cocultured with human osteoclasts for up to 20 weeks. RESULTS: Precultured cells were typically CD45(low/intermediate) CD38(high) CD138(high), CD19(-)CD34(-). After >6 weeks, the phenotype of cocultured myeloma cells consistently shifted to cells expressing CD45(intermediate/high) CD19(low) CD34(low). Expression of CD38 and CD138 were reduced to subpopulations with CD38(intermediate) and CD138(low) levels. Morphologically, cocultured plasma cells became plasmablastic. Blocking interleukin-6 activity did not affect the immature phenotype of myeloma cells. The effect of dexamethasone on myeloma cells cultured alone or in cocultures at baseline and after 6 weeks of coculture was determined. When baseline myeloma cells were cultured alone, dexamethasone significantly increased the percentage of apoptotic cells over the spontaneous rate. Conversely, myeloma cells recovered from cocultures had high survival rates and were resistant to dexamethasone-induced apoptosis. Long-term coculture of normal CD34-expressing hematopoietic stem cells (HSC) resulted in loss of CD34 expression, suggesting a common mechanism for osteoclast-induced myeloma and HSC plasticity. CONCLUSIONS: This study indicates that myeloma cells have plasticity expressed by their ability to reprogram, dedifferentiate, and acquire autonomous survival properties.

Antigens, CD19↗
PubMed1998

Phenotype interaction of apobec-1 and CETP, LDLR, and apoE gene expression in mice: role of apoB mRNA editing in lipoprotein phenotype expression.

Apolipoprotein (apo) B mRNA editing determines the amount of apoB-100 and apoB-48 produced. Surprisingly, apobec-1 knockout mice, which do not edit apoB, have an essentially normal lipoprotein phenotype. By selected cross-breeding of mice of different genotypes, we show in this report that inactivation of editing produces profound phenotypic effects in cholesteryl ester transfer protein (CETP) transgenic mice and in apoE and low density lipoprotein receptor (LDLR) knockout mice. Compared with mice with an apobec-1+/+ background, CETP expression in apobec-1-/- mice caused a doubling of the plasma apoB-100 concentration (from 3.5+/-0.6 to 8.8+/-1.9 mg/dL, P<.01) and a much greater shift of plasma cholesterol from HDL to IDL/LDL as assayed by fast protein liquid chromatography analysis; the ratio of non-HDL to HDL cholesterol was 0.47, 0.46, 0.76, and 1.43 in apobec-1(+/+)/CETP-/-, apobec-1(-/-)/CETP-/-, apobec-1(+/+)/CETP+/-, and apobec-1(-/-)/CETP+/- animals, respectively. Feeding of a Western-type diet further exaggerated the shift in this ratio. In LDLR-/- mice, inactivation of apobec-1 caused an approximately 200% rise in plasma apoB-100 concentration, an approximately 60% increase in apoE concentration, and a 70% increase in total plasma cholesterol, which resulted exclusively from an increase in non-HDL cholesterol. The exaggerated hypercholesterolemia involving the VLDL+LDL fractions was further enhanced by a Western-type diet. In contrast, in apoE-/- mice, inactivation of apobec-1 caused a massive increase (from <0.5 to 55.5+/-16.4 mg/dL) in plasma apoB-100 concentration but an approximately 55% reduction in hypercholesterolemia due to partial amelioration of the marked VLDL+IDL elevation. However, the difference in lipid profiles between apobec-1(+/+)/apoE-/- and apobec-1(-/-)/apoE-/- mice was abolished in a time-dependent manner as further increases in total plasma cholesterol were induced by a Western-type diet. Whereas apobec-1 inactivation in wild-type mice produced little or no change in lipoprotein phenotype, giving rise to speculation that apoB mRNA editing does not have significant effect on lipoprotein dynamics, we show herein that there is important gene-gene interaction between apobec-1 and the CETP, LDLR, and apoE loci, which is subject to further substantial modulation by environmental factors such as a Western-type diet in mice.

APOBEC-1 Deaminase↗
PubMed1999

Phenotype and genotype expression in pseudohomozygous factor VLEIDEN : the need for phenotype analysis.

The presence of a DNA mutation is frequently used to define a disease or a risk state. Because DNA typing has become easy and convenient in contrast to protein characterization, it is generally assumed that a mutation if present (or not) at the DNA level will be also present (or not) in the corresponding protein. However, discrepancies between phenotype and genotype can occur. A point mutation in the coagulation factor V gene (G1691-->A, resulting in an Arg506-->Gln amino acid substitution in the factor V molecule [factor VLEIDEN], leading to activated protein C resistance) is the most common genetic risk factor for familial thrombophilia. A pseudohomozygous factor VLEIDEN phenotype would occur if a heterozygous individual for factor VLEIDEN also did not express the "normal" (non-Leiden) factor V allele. However, to date, no data have been available to confirm the presence of only the factor VLEIDEN form in the plasma of these individuals. Platelet mRNA from 2 presumed pseudohomozygous patients and their family members was isolated, the amplified partial cDNAs were sequenced or restricted, and the allelic bands were quantified. Both patients were found to be heterozygous for the G1691-->A substitution at both the DNA and mRNA levels. The presence of either the normal or mutated form of factor V in the patients' plasmas was investigated using a monoclonal antibody to factor V that recognizes an epitope located between residues 307 and 506 of the factor Va heavy chain. No normal factor V could be detected in the plasmas of the 2 propositi. The present data demonstrate absence of a correlation between genotype at position 1691 (at the DNA and mRNA levels) and the corresponding phenotype data found in the plasmas of patients with pseudohomozygous factor VLEIDEN. Overall, these data suggest the existence of heterogeneous genetic "lesions," which interfere with factor V expression, processing, secretion, and/or stability. Because the presence of the factor VLEIDEN molecule in plasma is directly related to pathology, identification and quantification of the circulating forms of factor V in plasma may be required for the diagnosis of individuals with activated protein C resistance.

Adult↗
PubMed1992

The debrisoquine metabolic phenotype and DNA-based assays: implications of misclassification for the association of lung cancer and the debrisoquine metabolic phenotype.

Debrisoquine is an antihypertensive drug that is metabolized by cytochrome P4502D6. Deficient metabolism is inherited as an autosomal recessive condition. We previously reported in a case-control study that extensive metabolizers of debrisoquine were at greater risk of lung cancer compared to poor and intermediate metabolizers. Cloning of the gene that encodes P4502D6 (CYP2D6) led to the identification of both wild-type and mutant forms of the gene. Subsequently, a DNA-restriction fragment length polymorphism (RFLP) was identified, and a Southern hybridization-based test was developed in an attempt to define the genotype. When the DNA-RFLP test was applied to stored DNA from our study subjects there was neither a significant association with the metabolic phenotype nor an association with lung cancer. Further work has demonstrated that the wild-type gene, which was characterized by a 29-kb allele, can also contain mutations that result in nonfunctional or absent proteins. When these mutations are present, individuals exhibit the poor or intermediate metabolizer phenotype in spite of the presence of the 29-kb putative wild-type allele. Sequence determination of the mutants led to the development of techniques to exploit the polymerase chain reaction, which, together with Southern analysis, have been reported to detect as many as 95% of poor metabolizers. This technique is being used to examine the association of the extensive metabolizer genotype with lung cancer in the subjects from the case-control study. Preliminary results indicate a weak association between the homozygous wild-type genotype and lung cancer; in contrast, the extensive metabolizer phenotype is strongly associated with lung cancer in this subset.(ABSTRACT TRUNCATED AT 250 WORDS)

Case-Control Studies↗
PubMed2006

Lack of in vivo correlation between indinavir and saquinavir exposure and cytochrome P450 3A phenotype as assessed with oral midazolam as a phenotype probe.

STUDY OBJECTIVE: To investigate a potential correlation between exposure to oral midazolam, a commonly used cytochrome P450 (CYP) 3A probe, and saquinavir and indinavir exposure. DESIGN: Open-label, prospective, pharmacokinetic study. SETTING: Outpatient research center. SUBJECTS: Thirty-six healthy volunteers aged 22-50 years. INTERVENTION: Subjects received a single oral dose of midazolam 8 mg; 4 hours later, blood was drawn to determine their serum midazolam concentrations. Midazolam phenotyping was followed by successive administration of the protease inhibitors indinavir and saquinavir, with blood sampling and pharmacokinetic analyses performed at steady state. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic parameters of each protease inhibitor were evaluated to assess for a potential relationship with 4-hour concentrations of midazolam. No correlations between phenotype results for midazolam and any pharmacokinetic parameter for indinavir or saquinavir were identified (r(2)=0.00002-0.073). When the results were analyzed based on race, significant correlations were identified in five African-American subjects, including correlations between 4-hour midazolam levels and apparent oral clearance of saquinavir (r(2)=0.734, p=0.064), area under the plasma concentration-time curve from 0-8 hours (r(2)=0.914, p=0.011), minimum concentration (r(2)=0.857, p=0.024), and maximum concentration (r(2)=0.969, p=0.002). These findings for African-American subjects were not seen with indinavir. No correlation was found between indinavir and saquinavir pharmacokinetic parameters (r(2)=0.017-0.261). CONCLUSION: Oral midazolam was not a useful probe for predicting saquinavir or indinavir exposure at steady state. Reasons for the lack of correlation likely included differences between midazolam and protease inhibitor P-glycoprotein specificity, differences in the relative contribution of CYP3A5-mediated metabolism, and/or variation in intestinal and hepatic CYP3A specificity. The strong correlation between midazolam phenotype and pharmacokinetic parameters for saquinavir in African-American subjects indicated a racial difference in one or more of these confounding variables.

Administration, Oral↗
PubMed2005

Phenotypic characteristics of clinical isolates of Klebsiella pneumoniae & evaluation of available phenotypic techniques for detection of extended spectrum beta-lactamases.

BACKGROUND & OBJECTIVES: Identifying organisms that harbour extended spectrum beta lactamases (ESBLs) is a major challenge for a diagnostic clinical microbiology laboratory. Wide variety of ESBLs produced and lack of a sensitive phenotypic method for their detection make the detection of ESBLs difficult and is responsible for under-recognition. The present study was undertaken to evaluate phenotypic characteristics, initial screening tests and established confirmatory phenotypic methods for detection of ESBLs Klebsiella pneumoniae isolates prevalent in a hospital in north India. METHODS: One hundred, non-repeat clinical isolates of K. pneumoniae collected over a period of six months were included in the study. Susceptibilities of the isolates to 20 different antimicrobial agents were determined. Agar dilution and broth dilution methods were used to determine minimum inhibitory concentrations (MICs) of ceftazidime (CAZ) and cefotaxime (CTX). CAZ and CTX were used with and without clavulanic acid to detect ESBL harbouring isolates. Using agar dilution and broth dilution, MIC reduction of two and three doubling dilutions were evaluated as a criterion for ESBL harbouring isolates. Standard double disk synergy test (DDST) with disks placed at 30 mm and modified DDST with disks placed at 16 mm center-to-center distance, using at least two different third generation cephalosporins and combined disk method were also performed to detect ESBL harbouring isolates. RESULTS: Multi-drug resistance (resistance to three or more antimicrobials of different classes) was found among 94 per cent of the isolates. Pooling the results of all the three confirmatory techniques MIC reduction of >3 doubling dilutions using broth dilution method (using CTX and CAZ), combined disk method [(using CTX, ceftriaxone [(CRO), CAZ and aztreonam)] and standard DDST (using CTX, CRO, CAZ and aztreonam), revealed as many as 87 per cent of the isolates as ESBL producers. CTX had greater sensitivity in identifying isolates that harboured ESBLs. Modified DDST using CTX was as sensitive method as broth dilution method and combined disk method in detecting ESBL harbouring isolates. MIC reduction technique using agar dilution method and standard DDST had lowest overall sensitivity in detecting ESBLs. INTERPRETATION & CONCLUSION: Modified DDST using at least two different third generation cephalosporins was considered to be the best technique for detection of ESBL producing K. pneumoniae at our hospital. MIC reduction test with >2 doubling dilution reduction in MICs was found to be a better criterion than the presently recommended >3 doubling dilution reduction. For screening of potential ESBL producers, MIC determination using agar dilution was as good as that using broth dilution method. However, while performing MIC reduction test agar dilution method was found highly unreliable for detection of ESBL harbouring isolates.

Humans↗
PubMed1991

Haptoglobin phenotyping from older bloodstains by enzyme immunoassay and haptoglobin phenotypes within a Nebraska Caucasian population.

Enzyme immunoassay and Western blotting (electrophoretic) techniques were used to determine haptoglobin (HP) phenotypes from older bloodstains. Serum was collected from liquid blood and the HP phenotypes were determined. Bloodstains were prepared from these specimens and stored at various temperatures for several months. The stains were extracted and applied to gradient polyacrylamide gels. The Western blotting technique was used to achieve the transfer of HP bands from the gels to the nitrocellulose membranes. Enzyme immunoassay with goat anti-HP antiserum and rabbit anti-goat immunoglobulin peroxidase were used to identify the HP bands from the extracted samples. Enzyme immunoassay was found to be clearly more sensitive than o-dianisidine or o-tolidine in detecting HP bands from diluted serum samples. The haptoglobin frequency in a Caucasian population in Nebraska was calculated. The frequencies of Phenotypes 1, 2-1, and 2 were found to be 15.8, 48.4, and 35.8%, respectively.

Blood Preservation↗
PubMedDate not supplied

[Acute lymphoblastic Ph1-positive leukemia with a hybrid phenotype. The significance of the Ph1 anomaly and the hybrid phenotype].

The present paper reports on a case of acute lymphoblastic leukemia with t(9q+; 22q-) and surface markers specific of the B and T lymphoid line (hybrid phenotype). The fundamental (genotypical and phenotypical) and practical aspects (nosologic and therapeutical aspects) of this particular subtype of Ph1-positive acute leukemia and hybrid phenotype are discussed.

Adult↗
PubMed1993

The fragile-X phenotype. Computer assisted analysis of the dysmorphological features and discrimination from the Sotos phenotype.

Fragile-X and Sotos phenotypes may be difficult to distinguish. This is illustrated with a case report. Computer assisted phenotype analyses (MDDB), using the complete trait list of this patient, suggested the fragile-X diagnosis, which later was confirmed by molecular techniques. The results of corresponding phenotype analyses are summarized for 17 children with proven fragile-X, and 10 children with suggested Sotos syndrome.

Child↗
PubMed1997

Atypical skeletal changes in otopalatodigital syndrome type II: phenotypic overlap among otopalatodigital syndrome type II, boomerang dysplasia, atelosteogenesis type I and type III, and lethal male phenotype of Melnick-Needles syndrome.

We report on 2 cases of otopalatodigital syndrome type II (OPD II) with atypical skeletal changes, overlapping those of boomerang dysplasia, atelosteogenesis type I (AO I) and type III (AO III), and the lethal male phenotype of Melnick-Needles syndrome. One patient exhibited strikingly broad, bowed femora, which resembled those of boomerang dysplasia. The other patient possessed conspicuous undertubulation of the long bones, defective ossification of the spine, and severe undermineralization of the calvaria, which may have caused diagnostic confusion with AO I, AO III, and the lethal male phenotype of Melnick-Needles syndrome. OPD II is transmitted as an X-linked recessive trait, whereas AO I, AO III, and boomerang dysplasia are considered to result from a new dominant mutation, and Melnick-Needles syndrome is inherited as an X-linked dominant trait. Accordingly, differential diagnosis is mandatory to provide the affected families with adequate genetic counseling. Awareness of these skeletal changes in OPD II will prevent the misdiagnosis of this entity as other disorders. Furthermore, the phenotypic overlap among these disorders may expand the entities that constitute the OPD-Larsen dysplasia family proposed by Spranger [1985].

Abnormalities, Multiple↗
PubMed1999

Natural T cells in the human liver: cytotoxic lymphocytes with dual T cell and natural killer cell phenotype and function are phenotypically heterogenous and include Valpha24-JalphaQ and gammadelta T cell receptor bearing cells.

The adult liver contains lymphocytes with a unique phenotypic distribution compared to blood and other organs. We have characterized a human lymphocyte population that exhibits dual T cell and natural killer (NK) cell phenotype and function, denoted natural T (NT) cells, in nine normal adult liver specimens. Flow cytometry revealed that up to 55% (mean 27%) of hepatic (but <6% of peripheral) CD3+ lymphocytes expressed CD56, CD161 and/or one or more of the killer inhibitory receptors (KIR) p58.1, p58.2, p70 and CD94. NK function was attributed to the CD3+CD56+ cells by the demonstration that hepatic, but not peripheral, CD3+ lymphocytes could be induced to lyse NK-sensitive K562 target cells, while CD56- cells from both compartments could not. Three color flow cytometric analysis of fresh hepatic cells indicated that CD3+CD56+ NT cells can be either CD8+, CD4+ or CD4 CD8-, they express alphabeta or gammadelta T cell receptors (TCR) and CD161 and KIRs, but rarely CD16. Hepatic NT cells predominantly express the mature/activated CD45RO and CD56dim phenotypes. Analysis of mRNA production by isolated NT cells indicated a preferential usage of the invariant CD1-restricted Valpha24-JalphaQ TCR. The presence of such large numbers of chronically activated NT cells provides compelling evidence that the liver has unique immunoregulatory functions.

Adult↗
PubMedDate not supplied

Switch in chemokine receptor phenotype on memory T cells without a change in the cytokine phenotype.

Th1 and Th2 cells as defined by their cytokine profile are associated with the expression of the chemokine receptors CCR5 and CCR3, respectively. In committed human memory Th1 cells the cytokine profile is irreversibly expressed. However, it is not known if the chemokine receptor phenotypes of Th1 and Th2 cells are permanently associated to the cytokine profile or if it can be changed. To analyze the possibility of inducing a switch in chemokine receptor phenotype on memory Th cells we used differentiated memory Th cells isolated from synovial tissue (ST) samples of patients with rheumatoid arthritis (RA). Freshly isolated T cells, T-cell lines and T-cell clones from these tissues were manipulated with Th1 (interleukin (IL)-12 + anti IL-4) or Th2 (IL-4 + anti IL-12) inducing conditions. The surface expression of CCR5 and CCR3 was analyzed by flowcytometry and interferon (IFN)-gamma and IL-4 production by ELISA. A Th1-inducing cytokine environment increased the expression of CCR5 in Th1 cells and induced the expression of CCR5 in Th2 cells as compared to culture condition with only IL-2. Induction of CCR5 expression on Th2 clones was associated with secretion of some IFN-gamma. Moreover, the Th2-associated chemokine receptor CCR3 could be expressed on both Th1-dominant cell lines, and clones of Th1 and Th0 type after culture conditions with IL-4. This expression of CCR3 was associated with a reduced IFN-gamma production, but no IL-4 production could be induced. The IL-4-treated Th1 clones had a reduced migratory capacity against chemokines produced by ST cells compared to nonmanipulated T-cell clones. In contrast, the same IL-12-treated Th1 clones showed an increased migratory potential. Induction of the Th2-associated marker CCR3 on memory Th1 cells demonstrates that a change in chemokine receptor phenotype related to the Th2 type can be induced on terminally differentiated Th1 cells, without a change in the cytokine profile.

Arthritis, Rheumatoid↗
PubMed2000

H-ras, but not N-ras, induces an invasive phenotype in human breast epithelial cells: a role for MMP-2 in the H-ras-induced invasive phenotype.

Elevated p21ras expression is associated with tumor aggressiveness in breast cancer including the extent of invasion into fat tissues, infiltration into lymphatic vessels and tumor recurrence. In the present study, we have examined the roles of H-ras and N-ras, members of the human ras gene family, in the pathogenesis of breast cancer. We show that H-ras, but not N-ras, induces an invasive phenotype in human breast epithelial cells (MCF10A) as determined by the Matrigel invasion assay, whereas both H-ras and N-ras induce anchorage-independent growth, as shown by soft agar assay. We examined the effects of H-ras and N-ras activation on the expression of MMP-2 and MMP-9, which can degrade type IV collagen, the major structural collagen of the basement membrane. We show that MMP-2 is efficiently induced by H-ras, whereas MMP-9 induction is more prominent in N-ras-activated MCF10A cells. We also show that H-ras-mediated invasiveness is significantly inhibited when the expression of MMP-2 is down-regulated, using an oligodeoxyribonucleotide complementary to the MMP-2 mRNA, or when MMP-2 activity is blocked by its inhibitor TIMP-2 (tissue inhibitors of matrix metalloproteinase-2). Our results show that the H-ras-induced invasive phenotype is associated more closely with the expression of MMP-2 in human breast epithelial cells, rather than the induction of MMP-9 expression, as shown previously for rat embryonic fibroblasts.

Breast Neoplasms↗
PubMed2003

Molecular, biochemical, and phenotypic analysis of a hemizygous male with a severe atypical phenotype for X-linked dominant Conradi-Hunermann-Happle syndrome and a mutation in EBP.

X-linked dominant Conradi-Hunermann-Happle syndrome (CDPX2; MIM 302960) is a rare chondrodysplasia punctata primarily affecting females. CDPX2 is presumed lethal in males, although a few affected males have been reported. CDPX2 is a cholesterol biosynthetic disorder due to 3-beta-hydroxysteroid-delta8,delta7-isomerase deficiency caused by mutations in the emopamil binding protein (EBP) gene. A 2.5-year-old Caucasian male was followed from the age of 6 weeks and noted to have significant developmental delay, hypotonia, seizures, and patchy hypopigmentation. Multiple congenital anomalies included a unilateral cataract, esotropia, crossed renal ectopia, stenotic ear canals, and failure to thrive, requiring G-tube placement. Multiple minor anomalies and ptosis were noted. No skeletal asymmetry or chondrodysplasia punctata were noted on skeletal survey at 6 weeks and 13 months. An extensive genetic work-up including cholesterol (126-176 mg/dl) and 7-dehydrocholesterol was unrevealing. However, the levels of 8(9)-cholestenol and 8-dehydrocholesterol were mildly increased in plasma, which was confirmed in cultured fibroblasts. This prompted molecular analysis of the EBP gene, which revealed a novel hemizygous (nonmosaic) mutation in exon 2 (L18P). Two restriction digests were developed that confirmed this mutation in skin fibroblasts, blood, and buccal cells (all nonmosaic). We determined that the patient's mother (adopted) also has the L18P mutation enabling prenatal diagnosis of a normal male fetus. She has normal stature, no asymmetry, no cataracts at this time, and has a patch of hyperpigmentation on her chest best visualized on Woods lamp examination, characteristic of CDPX2. The mild maternal phenotype has been described previously. However, this nonmosaic missense mutation has resulted in a severe phenotype in her surviving son.

Carrier Proteins↗
PubMed2005

Phenotypic expression of genotype-phenotype correlation in cystic fibrosis patients carrying the 852del22 mutation.

Currently, more than 1,000 mutations have been identified in the cystic fibrosis transmembrane regulator (CFTR) gene. While some mutations are common worldwide, the majority are restricted in certain ethnic groups. We have found that in Southern Italy, the 852del22 mutation is well represented with a frequency of 3.5%. We have screened, by reverse dot blot, denaturing gradient gel electrophoresis (DGGE), and gene sequencing, the entire coding regions of CFTR gene in 371 consecutive cystic fibrosis (CF) patients from Southern Italy and have identified 17 patients carrying rare genotypes, among which 13 [6 M; median age 21.7 years (range: 4.5-47.7 years)] carry the 852del22 mutation. To assess the phenotypic expression of CF in patients with the 852del22 mutations we have compared these patients with a group of age and gender matched patients homozygous for the DeltaF508 mutation [n = 34; 19 M; median age 19.9 years (range: 3.8-34.6 years)]. Overall, we found no difference in terms of complications, patient survival (17.6% vs. 30.7%; P = NS), estimated time needed to develop a severe lung disease (22.1 vs. 24.5 years; P = NS), nutritional status, and rate of infection or colonization by most common pathogens between patients in the two groups. Finally, we have found that a late diagnosis was associated with a poor outcome (severe lung disease) regardless of genotype. Our data show that 852del22 mutation results in a phenotypic expression of disease as severe as that determined by the more typical DeltaF508 and, as in the latter case, there is no strict genotype/phenotype correlation.

Adolescent↗