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PubMed1993

[Detection of the phenotypes of resistance of enterobacteriaceae to aminoglycosides with ATB Plus Expert System].

ATB Plus Expert (Biomérieux SA) is an expert system which has been developed to perform an interpretative reading of ATB susceptibility tests. The system was tested on the results obtained for 217 strains of enterobacteriaceae. These strains were selected in order to cover a maximum of bacterial species and resistance mechanisms. The isolates were tested on rapid ATB E, rapid ATB G-, rapid ATB Ur, ATB G- and ATB Ur strips. In parallel, a disc diffusion susceptibility test was performed with 5 discs of aminoglycosides (kanamycin, gentamicin, tobramycin, netilmicin, amikacin) and the interpretation was carried out according to the criteria usually followed. Of the 217 strains tested, 122 showed a resistance phenotype. Only the rapid ATB E strips included kanamycin and allowed the detection of APH(3') phenotypes. Amikacin was not included in the ATB Ur strip, consequently it was impossible to discriminate AAC(3)-II and AAC(6') + AAC(3)-I phenotypes. 12 strains did not grow within 5 hours using the rapid ATB methodology. Not taking into account the problems previously encountered, different phenotypes between the 6 susceptibility tests were found for 16 strains. In 5 cases the expert system detected an anomaly instead of the correct phenotype, and in 3 cases of unknown phenotypes, the answers were variable. In the other cases, the main difficulty was the detection of the isolated resistance to gentamicin (AAC(3)-I phenotype). The expert system automatically corrects the susceptibility test result according to the phenotype observed.

Amikacin↗

PubMed1993

Clonal analysis of the expression of multiple transformation phenotypes and tumorigenicity by morphologically transformed 10T1/2 cells.

Seventy-five clonal populations of morphologically transformed 10T1/2 cells were established from independent Type II and Type III foci that were of spontaneous origin or were induced by the carcinogenic agents N-methyl-N'-nitro-N-nitrosoguanidine, benzo(a)pyrene diol epoxide-I, and 3-methylcholanthrene. Clonal populations were characterized for expression of selected transformation phenotypes, including growth to elevated saturation density before cessation of proliferation, anchorage independence, ability to reconstruct foci when plated in the presence of wild-type 10T1/2 cells, and tumorigenicity. Forty-one % of the clonal populations expressed only the phenotype of morphological transformation, while 20% expressed all of the transformation phenotypes, including tumorigenicity, in addition to morphological transformation. The remaining clonal populations expressed varying combinations of one or more of the four transformation phenotypes. Clonal populations expressing almost all of the 16 possible combinations of the transformation phenotypes were observed, suggesting that the individual phenotypes segregated independently. Morphological transformation alone was a poor indicator of tumorigenicity, correctly predicting the tumorigenic potential of only 37% of the clonal populations. Among morphologically transformed clonal populations, coexpression of anchorage independence correctly predicted the tumorigenicity of 81% and coexpression of reconstruction of foci on a confluent lawn of wild-type cells correctly predicted the tumorigenicity of 91%. The probability that a morphologically transformed clonal population was tumorigenic correlated with the total number of transformation phenotypes expressed. Expression of the transformation phenotypes differed between tumorigenic and nontumorigenic clonal populations but not between clonal populations established from Type II and Type III foci. Tumorigenicity varied among transformed clonal populations that were induced by the different carcinogenic agents or were of spontaneous origin but did not differ between clonal populations established from Type II and Type III foci.

Animals↗

PubMed1996

[A pathological study on phenotype differentiation and its significance in pulmonary large cell carcinoma].

This study was designed to find the differentiated phenotype and its clinicopathological significance in pulmonary large cell carcinoam (PLCC) by immunohistochemical methods using a panel of antibodies related to the phenotype differentiation: high molecular weight cytokeratin, low molecular weight cytokeratiin, secretory component, chromogranin A and synaptophysin in 60 cases of PLCC. The results demonstrated that all cases of PLCC possessed monophasic, biphasic and triphasic phenotype differentiation features respectively, including squamous (4 cases), adenomatous (20 cases), neuroendocrine (19 cases), adenosquamous (11 cases); and the the coexistence of adenomatous, squamous and neuroendocrine (6 cases). The median survival time was different between patients with various differentiated phenotypes of PLCC. There was a statistically significant difference (P < 0.05) in survival between neuroendocrine and adenomatous phenotypes. The results of this study implies that: (1) PLCC expressed different phenotypes of differentiation, (2) phenotypes of neuroendocrine differentiation has a poor prognosis, (3) it is necessary to classify PLCC according to the phenotype differentiation.

Carcinoma, Non-Small-Cell Lung↗

PubMed1997

Retrospective cohort study of changes in hip joint phenotype of dogs in the United States.

OBJECTIVE: To determine whether there had been a significant improvement in hip joint phenotype of dogs in the United States by comparing results of evaluations done by the Orthopedic Foundation for Animals of dogs born between 1972 and 1980 with those of dogs born between 1989 and 1992 and determining whether there had been an increase in the percentage of dogs classified as having excellent hip joint phenotype. DESIGN: Retrospective cohort study. SAMPLE POPULATION: 270,978 evaluations. PROCEDURE: Numbers and percentages of dogs classified as having excellent hip joint phenotype during each period and change between periods in percentages of dogs classified as having excellent hip joint phenotype were calculated. RESULTS: Percentage of dogs born between 1989 and 1992 that were classified as having excellent hip joint phenotype (15,289/143,668; 10.64%) was significantly higher than percentage of dogs born between 1972 and 1980 that were classified as having excellent hip joint phenotype (9,960/127,310; 7.82%). The increase in percentage of dogs classified as having excellent hip joint phenotype was significantly higher for male (51%) than for female (27%) dogs. CLINICAL IMPLICATIONS: Results suggest that there has been an improvement in the hip joint phenotype of dogs in the United States between the 1970s and early 1990s and that the improvement has been greater among male than among female dogs.

Animals↗

PubMed1998

Lp (a) levels and apo (a) phenotypes in urban black South African men.

OBJECTIVE: To investigate the lipoprotein (a) (Lp (a)) levels and apolipoprotein (a) (apo (a)) phenotypes in a group of urban black South African men. DESIGN: Cross-sectional design. SETTING: Lead acid battery plant, East London, Eastern Cape. PARTICIPANTS: Blood samples from a study on the association between lead and renal failure were kindly donated for the present study and 111 of the donors participated (K Steyn-personal communication). OUTCOME MEASURES: Lp (a) levels and apo (a) phenotypes. RESULTS: Three groups were identified: those with normal (< 300 U/l), intermediate (300-700 U/l) and high (> 700 U/l) plasma Lp (a) concentrations. Nine apo (a) phenotypes and 26 combinations thereof could be discerned. Apart from the single- and double-band phenotypes described before, triple-band phenotypes were also present. As the Lp (a) values increased, the relative frequency of the single-band phenotype decreased, whereas the relative frequency of the double-band phenotype increased. The relative frequency of the triple-band phenotype was highest in the group with high Lp (a) concentrations. No correlation was evident between the size of the apo (a) isoforms and the Lp (a) concentrations. CONCLUSIONS: Raised plasma Lp (a) levels have been associated with coronary heart disease (CHD). In addition, it has been proposed that the apo (a) gene determined plasma Lp (a) concentrations. These studies were performed using plasma from white subjects. CHD is uncommon in black South Africans. The reason may be that, given the lack of relationship between the size of the apo (a) isoforms and the Lp (a) concentrations observed in the present study, factors other than the isoform size may determine the Lp (a) levels in this particular ethnic group.

Apolipoproteins↗

PubMed1994

The phenotype of L-CFU and its correlation with the immunological characteristics of the blast cell population in AML.

The membrane phenotype of AML clonogenic cells (L-CFU) was analyzed in 19 AML patients using an in vitro culture technique after a complement-mediated lysis assay employing a panel of six monoclonal antibodies (McAb) -HLA-DR, FMC56 (CD9), FMC27 (CD9), CD14, CD15, CD41a-. Our results show that L-CFU has a heterogeneous but immature phenotype lacking on the expression of differentiation antigens (CD14, CD15, CD41a). In addition, we observed that the L-CFU phenotype is different from that of the whole blast cell population. Interestingly, L-CFU showed a higher expression of HLA-DR antigens with respect to their progeny. Upon analyzing whether the L-CFU phenotype was related to both the morphological and immunological features of AML blast cells, it was observed that, while there is no correlation with the FAB classification, there was a partial relationship between the immunological phenotype of AML blast cells and that of L-CFU. Accordingly, the more immature AML cases showed a more differentiated L-CFU phenotype (HLA-DR+, CD9+, FMC27+) when compared with cases with a more mature blast cell phenotype. These results suggest that those AML cases with a relatively immature myeloblastic phenotype may arise from a progenitor cell that has undergone partial differentiation and that is unable to acquire myeloid differentiation antigens, while those AML cases with mature blast cells might emerge from a very early L-CFU that has the capacity to undergo a greater degree of differentiation.

Antigens, CD↗

PubMed2002

Multiple mechanisms generate HLA class I altered phenotypes in laryngeal carcinomas: high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21.

Major histocompatibility complex (MHC) class I loss or downregulation in cancer cells is a major immune escape route used by a large variety of human tumors to evade anti-tumor immune responses mediated by cytotoxic T lymphocytes. Multiple mechanisms are responsible for such HLA class I alterations. However, the precise frequency of these molecular defects has not been clearly determined in tumors derived from specific tissues. To analyze such defects we aim to define the major HLA class I-altered phenotypes in different tumor types. In this paper we report on HLA class I expression in 70 laryngeal carcinomas. We used immunohistological techniques with a highly selective panel of anti-HLA monoclonal antibodies (mAb), and polymerase chain reaction (PCR) microsatellite amplification of previously selected microsatellite markers (STR) located in chromosome 6 and 15. DNA was obtained from microdissected tumor tissues and surrounding stroma to define the loss of heterozygosity (LOH) associated with chromosome 6p21. Our results showed that LOH in chromosome 6 produced HLA haplotype loss (phenotype II) in 36% of the tumors. In addition, HLA class I total loss (phenotype I) was found in 11%; HLA A or B locus downregulation (phenotype III) was detected in 20%; and HLA class I allelic loss (phenotype IV) in 10% of all cases. We sometimes observed two or more associated mechanisms in the same HLA-altered phenotype, such as LOH and HLA total loss in phenotype I. In only 23% of tumors it was not possible to identify any HLA class I alteration. We conclude that the combination of immunohistological techniques and molecular analysis of tumor DNA obtained from microdissected tumor tissues provides a means for the first time of determining the actual frequency of the major HLA class I-altered phenotypes in laryngeal carcinomas.

Antigens, Neoplasm↗

PubMed1995

Lewis phenotypes and the insulin resistance syndrome in young healthy white men and women.

An increased risk of ischemic heart disease in men with the Lewis blood group phenotype Le(a-b-) has been reported. It has been suggested that the Le(a-b-) phenotype is a genetic marker of the insulin resistance syndrome. To examine whether Le(a-b-) confers the insulin resistance syndrome, we studied a random sample of unrelated healthy young white men and women living in Copenhagen (n = 380, 18 to 32 years). All individuals had their insulin sensitivity estimated using Bergman's minimal model (intravenous glucose in combination with tolbutamide) and systolic blood pressure (SBP) was measured with a London School of Hygiene Sphygmomanometer. A number of anthropometric measurements including body mass index (BMI, kilograms/meters squared) and biochemical characteristics were performed. The Lewis blood group typing was carried out on erythrocytes. Twenty-one men had the Le(a-b-) phenotype. Compared to all other men (N = 165), the Le(a-b-) men had a significantly higher SBP (6 mm Hg, P = .0024). They also had higher values of BMI (8%, P = .016), total body fat mass (25%, P = .015), fasting values of serum insulin (32%, P = .006), serum C-peptide (20%, P = .029), and plasma glucose (8%, P = .003). The fasting values of serum lipids, plasminogen activator inhibitor (PAI-1) activity, tissue plasminogen activator (t-PA) antigen, and insulin sensitivity did not differ between Le(a-b-) men and men with other Lewis phenotypes. Altogether 194 women participated in the study of which 21 women had the Le(a-b-) phenotype. Except for a lower PAI-1 activity (45%, P = .044), no values differed between Le(a-b-) women and women with other Lewis phenotypes. The women were also stratified according to use of oral contraceptives. Le(a-b-) women using oral contraceptives (N = 8) had a significantly lower plasma level of fasting PAI-1 activity (P = .029) and t-PA antigen (P = .004) compared to women using oral contraceptives without the Le(a-b-) phenotype (N = 42). Our data support the hypothesis that Le(a-b-) men exhibit features of the insulin resistance syndrome, including higher levels of BMI, SBP, and fasting levels of serum insulin and plasma glucose. In young women no signs of the insulin resistance syndrome were found in subjects with the Le(a-b-) phenotype.

Adolescent↗

PubMed2002

Influence of the ORM1 phenotypes on serum unbound concentration and protein binding of quinidine.

BACKGROUND: Only unbound or free drug in plasma can be transported to its site of action. The fraction of unbound drug in plasma varies widely for highly bound drugs among individuals. The genetic polymorphism of orosomucoid (ORM) could be related to the interindividual variability in plasma binding of basic drugs, as ORM is the transport protein for these drugs in plasma. The ORM is a major binding protein in plasma for various basic drugs and is coded by two loci, ORM1 and ORM2, which are closely linked on chromosome 9q31-->34.1. ORM1 locus is highly polymorphic and the ORM2 locus is monomorphic in most population. METHODS: Twenty-eight healthy volunteers were selected with three ORM1 phenotypes, containing homozygotes ORM1 F1 (n=10) and ORM1 S (n=8), and heterozygote ORM1 F1S (n=10), identified by isoelectric focusing on polyacrylamide gels followed immunoblotting after desialylation of sera. After a single oral dose of quinidine 200 mg, serum total (HPLC) and unbound concentrations in ultrafiltrate (ultrafiltration/HPLC) were determined, and the pharmacokinetic parameters and protein binding rate were calculated. RESULTS: Serum concentrations of ORM (553.8-573.2 mg/l) and albumin proteins (57.5-58.4 mg/l) were similar in the three groups (P>0.05). Unbound quinidine concentration in ORM1 F1 phenotype subjects was higher than that in ORM1 S and ORM1 F1S phenotype; the free drug percentage for the subjects with ORM1 F1 phenotype (19.79%) was twice as high as that with ORM1 S phenotype (10.96%) (P<0.01) at 24 h after administration of oral quinidine when the state of disposition equilibrium occurred. The elimination t(1/2) values and the other pharmacokinetic parameters of quinidine were not affected by the different ORM1 phenotypes. CONCLUSIONS: Different ORM1 phenotypes may affect the disposition of quinidine, a basic drug, rather than its hepatic metabolism and elimination. The functional heterogeneity of ORM1 could be responsible for the differences in plasma binding of quinidine. Therefore, monitoring of the unbound quinidine concentration would be important for the patients with different ORM1 phenotypes who are treated with quinidine.

Adult↗

PubMed1994

Dose and time dependence of the cellular phenotype in rat hepatic preneoplasia and neoplasia induced by single oral exposures to N-nitrosomorpholine.

The dose and time dependence of the cellular phenotype in preneoplastic and neoplastic liver lesions was studied quantitatively in groups of male Sprague-Dawley rats exposed to single oral doses of 0, 200 and 320 mg/kg body wt of N-nitrosomorpholine (NNM) and killed at different time points between 7 and 80 weeks. Compared with the untreated controls, NNM-treated rats showed a dose- and time-dependent increase in the total number and volume of preneoplastic foci of altered hepatocytes (FAH) and in the incidence of hepatocellular adenomas (HCA). In controls, two major phenotypes of FAH were found in low numbers, namely clear and combined clear/acidophilic cell foci which both store excessive amounts of glycogen. The increase in the total number and volume of FAH by single doses of NNM was associated with changes in their cellular phenotype. Clear cell foci were more frequent in the lower dose group than in the higher dose group throughout the observation period. With the exception of the first 15 weeks, combined clear/acidophilic cell foci represented the most frequent phenotype at both dose levels and all time points studied. In contrast, mixed cell foci, which were completely lacking in controls, showed a high relative frequency after a single NNM dose of 320 mg/kg body wt throughout the observation period, but emerged at later time points and in lower numbers when the lower single dose was given. At both dose levels, mixed-cell foci represented the largest phenotype of FAH; their volume fraction correlated positively with the incidence of HCA, indicating a direct precursor-product relationship between these lesions. The size class distribution and temporal appearance of the different phenotypes of FAH and of the adenomas suggest a progression-linked phenotypic instability of the altered cellular phenotypes, resulting in a predominant sequence of cellular changes which leads from glycogenotic clear and acidophilic cell foci to mixed and basophilic cell populations, the latter being poor in glycogen. In addition to these types of FAH, tigroid cell foci, which were very rare in controls, developed in significantly greater numbers after single-dose treatment with NNM at both dose levels. This type of focus may either represent a side lineage of the predominant lineage or an intermediate stage in an alternative lineage of hepatocellular changes, but in any case has the potential to give rise to HCA.

Administration, Oral↗

PubMed2005

Maternal hyperinsulinemia predisposes rat fetuses for hyperinsulinemia, and adult-onset obesity and maternal mild food restriction reverses this phenotype.

We have previously shown that artificial rearing of newborn female rat pups on a high-carbohydrate (HC) milk formula resulted in chronic hyperinsulinemia and adult-onset obesity (HC phenotype) and that the maternal HC phenotype was transmitted to their progeny (2-HC rats) because of fetal development in the HC female rat. The aims of this study were to investigate 1) the fetal adaptations that predisposed the progeny for the expression of the HC phenotype in adulthood and 2) whether the transfer of the HC phenotype to the progeny could be reversed by maternal food restriction. Fetal parameters such as plasma insulin and glucose levels, mRNA level of preproinsulin gene, pancreatic insulin content, and islet insulin secretory response in vitro were determined. On gestational day 21, 2-HC fetuses were hyperinsulinemic, had increased insulin content and mRNA level of the preproinsulin gene in their pancreata and demonstrated an altered glucose-stimulated insulin secretory response by isolated islets. Modification of the intrauterine environment in HC female rats was achieved by pair feeding them to the amount of diet consumed by age-matched control rats from the time of their weaning. This mild dietary restriction reversed their HC phenotype and also prevented the development of the HC phenotype in their progeny. These findings show that mal-programming of the progeny of the hyperinsulinemic-obese HC female for the expression of the HC phenotype is initiated in utero and that normalization of the maternal environment in HC female rats by mild food restriction resulted in the normal phenotype in their progeny.

Animals↗

PubMed2001

Aberrant phenotypes in acute myeloid leukemia: a high frequency and its clinical significance.

BACKGROUND AND OBJECTIVES: Immunophenotyping is an essential method for diagnosis and classification of acute myeloid leukemias (AML), and its extensive use could identify blast cell subpopulations with aberrant phenotypes rarely seen in normal myelopoiesis. The aberrant phenotypes have been correlated with clinical, morphological and prognostic features but their occurrence in AML differs in the various studies. DESIGN AND METHODS: In this study, we analyzed 35 cases of AML, examining them for aberrant phenotypes by multiparametric flow cytometry. Co-expression of lymphoid-associated markers in myeloblasts and asynchronous antigen expression were correlated with clinical features. RESULTS: Aberrant phenotypes were found in 88.6% of the cases studied. In this group, cross-lineage antigen expression was present in 34.3% and asynchronous expression in 82.4% of the cases. CD7 was the most frequent lymphoid-associated antigen. Among the cases of asynchronous antigen expression, the most frequent phenotype was CD117(+) and/or CD34(+) in association with CD11c(+), followed by CD15(+) and CD65(+), corresponding to 67.6%, 61.7 and 50.0% of the cases, respectively. Twenty out of 33 patients were available for complete remission assessment. The CD117(+) CD15(+) phenotype correlated significantly with complete remission achievement and with the lack of unfavorable chromosome associations. INTERPRETATION AND CONCLUSIONS: We conclude that aberrant phenotypes, as they are described here, are present in the great majority of cases of AML, asynchronous antigen expression being the most frequent example; and that CD117(+) CD15(+) phenotype shows a relevant association with clinical prognosis.

Acute Disease↗

PubMed1999

Stability of naive and memory phenotypes on resting CD4 T cells in vivo.

The reliable identification of naive and memory CD4 T cells is critical to understanding the cellular basis of immunological memory. However, it has long been a controversial issue whether naive and memory phenotypes are stable among resting CD4 T cells in the absence of overt stimulation or whether the proposed memory phenotype is a transient, reversible one that represents recently activated cells. In this study, adoptively transferred, purified populations of naive or memory phenotype CD4 T cells are monitored over time to assess the stability of phenotypes and the functional capabilities of transferred cells. Studying both TCR transgenic and nontransgenic CD4 T cell populations allows one to control for the capacity to respond to environmental Ags in vivo. Several findings are reported. The first is that in the absence of Ag, both naive and memory phenotypes remain unchanged over time. Second, when changes are seen in populations of transferred naive phenotype CD4 T cells, they take place only when there is a potential for antigenic challenge, suggesting that it is an Ag-driven event. Furthermore, when a change from naive to memory phenotype is observed, these transferred donor cells also function as memory cells. Third, the ability of memory CD4 T cells to retain the memory phenotype is independent of specific Ag.

Adoptive Transfer↗

PubMed2026

Hybrid genome assembly and phenotypic assays reveal carbohydrate metabolism diversity in Lacticaseibacillus strains.

Investigation of carbohydrate metabolism in lactic acid bacteria is essential for the rational selection of strains for fermentation processes, particularly in emerging applications involving non-conventional substrates or building of synthetic microbial consortia. However, establishing robust genotype-phenotype relationships remains challenging, as gene presence alone often fails to explain observed metabolic traits without considering the genomic context and regulatory architecture. In the present study, we combined hybrid genome assembly (Illumina and Oxford Nanopore) with high-throughput phenotype profiling (Biolog GENIII and PM2A) to investigate carbohydrate utilization in five Lacticaseibacillus strains. Phenotypic assays revealed clear intra- and inter-specific variability in substrate utilization. We therefore investigated whether such differences could be attributed to the organization and regulatory context of carbohydrate-associated loci, rather than to gene presence alone. Functional annotation based on COG and CAZyme databases revealed candidate genomic regions potentially involved in carbohydrate metabolism. Comparative analysis between predicted and experimentally observed substrate usage highlighted specific loci associated with carbohydrate utilization profile. The trehalose (tre) operon was conserved across all strains, while at least two distinct cellobiose-associated loci were detected in each genome. Despite the presence of these loci, L. paracasei strains were unable to metabolize cellobiose, a phenotype likely linked to the presence of a downstream TetR-type transcriptional repressor within the cellobiose (cel) operon. Additionally, a genomic region uniquely found in L. rhamnosus strains was associated with gentiobiose utilization, consistent with phenotypic observations. Overall, these findings highlight the importance of integrating phenotypic validation with complete genome context to support the identification of candidate structural and regulatory determinants of carbohydrate utilization in lactic acid bacteria. KEY POINTS: • Phenotype microarrays reveal metabolic traits of interest in isolated strains. • Regulatory context is key to understanding carbohydrate metabolism differences. • Basis of subspecies-dependent cellobiose metabolism in L. paracasei is provided.

Carbohydrate Metabolism↗

PubMed2025

Predicting natural variation in the yeast phenotypic landscape with machine learning.

Most organismal traits result from the complex interplay of many genetic and environmental factors, making their prediction difficult. Here, we used machine learning (ML) models to explore phenotype predictions for 223 traits measured across 1011 genome-sequenced Saccharomyces cerevisiae strains isolated worldwide. We benchmarked a ML pipeline with multiple linear and non-linear models to predict phenotypes from genotypes and gene expression, and determined gradient boosting machines as the best-performing model. Gene function disruption scores and gene presence/absence emerged as best predictors, suggesting a considerable contribution of the accessory genome in controlling phenotypes. The prediction accuracy broadly varied among phenotypes, with stress resistance being easier to predict compared to growth across nutrients. ML identified relevant genomic features linked to phenotypes, including high-impact variants with established relationships to phenotypes, despite these being rare in the population. Near-perfect accuracies were achieved when other phenomics data mostly in similar conditions were used, suggesting that useful information can be conveyed across phenotypes. Overall, our study underscores the power of ML to interpret the functional outcome of genetic variants.

Genetic Variation↗

PubMed2025

Genotype-phenotype correlations with autism spectrum disorder-related traits in noonan syndrome and noonan syndrome with multiple lentigines: a cross-sectional study.

BACKGROUND: Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are neurodevelopmental conditions caused by genetic variants leading to upregulated signaling in the RAS-MAPK pathway. While previous research has focused on genetic variability in cognitive and cardiac phenotypes, behavioral phenotypes, and their correlations across genetic variants and within the PTPN11 gene remain poorly characterized. METHODS: This study included 121 individuals with NS (PTPN11: 88, SOS1: 18, RAF1: 6, KRAS: 2, RIT1: 3, NRAS: 2, LZTR1: 2, SOS2: 1) and seven individuals with NSML (PTPN11), compared to age- and sex-matched typically developing (TD) (N = 71). Behavioral questionnaires assessed social responsiveness and ASD-related traits (using SRS-2), and emotional problems (using CBCL) to identify genetic variant-specific behavioral profiles. Biochemical profiling of SHP2 activity in PTPN11-associated NS variants examined genotype-phenotype relationships. RESULTS: Compared to TD individuals, those with PTPN11-associated NS, NSML, and SOS1-associated NS exhibited clinically elevated scores, indicating increased ASD-related behaviors, poorer social functioning, and heightened emotional problems. Genetic variant comparisons revealed that individuals with PTPN11-associated NS and NSML exhibited greater ASD-related challenges than those with RAF1. Individuals with NSML exhibit elevated attention problems compared to all other genetic groups. Logistic regression results suggested each one-unit increase in SHP2 fold activation for PTPN11-associated NS corresponded to a 64% higher likelihood of markedly elevated restricted and repetitive behaviors, suggesting genotype-phenotype links. LIMITATIONS: Small sample sizes for rarer variants, leading to unequal group sizes across subgroups, with PTPN11 variants comprising most of the NS group. Future research should address these sampling constraints and conduct functional studies to clarify variant impacts. Longitudinal assessments could elucidate behavioral phenotype trajectories. CONCLUSIONS: This study underscores the importance of genetic variant-specific research to understand unique behavioral phenotypes in NS and NSML. Our findings indicate a higher risk for ASD-related symptoms in PTPN11-associated NS and NSML compared to other variants. Additionally, individuals with PTPN11-associated NS and higher SHP2 fold activation exhibited greater impairments in restricted and repetitive behaviors, suggesting SHP2 activation variations may contribute to phenotypic variability. By linking ASD-related symptoms to biochemical predictors in PTPN11-associated NS, this study may inform future targeted treatment approaches.

Humans↗

PubMed2004

The parkinsonian phenotype of spinocerebellar ataxia type 2.

BACKGROUND: We recently reported that spinocerebellar ataxia type 2 (SCA2) caused familial parkinsonism in 2 brothers with predominant symptoms of resting tremor, rigidity, and bradykinesia that responded to levodopa. OBJECTIVE: To investigate SCA2 as the possible cause of familial parkinsonism in our series and subsequently to analyze the correlation between the clinical manifestation and CAG repeat size in the ataxin-2 gene product. PATIENTS: One hundred thirty patients from 41 families with familial parkinsonism were examined for SCA2. Another 8 patients with the classic ataxic phenotype of SCA2 from 6 families were the control group. DESIGN: The length of expanded CAG repeat was analyzed by means of polymerase chain reaction. The clinical data and genetic findings in the parkinsonian phenotype were then compared with those in the ataxic phenotype. RESULTS: We found expanded CAG repeats in the ataxin-2 gene product in 7 patients from 4 families with parkin-sonism, which was about 10% of our familial parkinsonism series. The parkinsonian phenotype was characterized by resting tremor, rigidity, and bradykinesia. Only mild dysarthria, ataxic gait, and instability were noted, particularly in the late stage. Patients with the parkinsonian phenotype had an older mean +/- SD age of symptom onset (45.8 +/- 13.9 years) and shorter mean +/- SD abnormal CAG length (36.2 +/- 1.1 repeats) than did those with the ataxic phenotype (26.9 +/- 11.0 years and 43.1 +/- 3.2 repeats). Parkinsonian SCA2 responded well to levodopa. CONCLUSIONS: We conclude that SCA2 is a minor cause of familial parkinsonism, particularly in Taiwan. The parkinsonian phenotype is associated predominantly with a shorter abnormal range of CAG repeat lengths and older onset age. Because of the clinical resemblance among familial parkinsonisms, we suggest that SCA2 should be excluded in cases of familial parkinsonism.

Adolescent↗

PubMed2000

Haplotype-phenotype correlation in Fukuyama congenital muscular dystrophy.

In typical Fukuyama congenital muscular dystrophy (FCMD), peak motor function is usually only unassisted sitting or sliding on the buttocks, though a few patients are able to walk at some point. However, a few patients have a severe phenotype and never acquire head control. In addition, it is clinically difficult to differentiate this severe FCMD from Walker-Warburg syndrome (WWS) or from muscle-eye-brain disease (MEBD). In order to establish a genotype-phenotype correlation, we performed haplotype analysis using microsatellite markers closest to the FCMD gene (FCMD) in 56 Japanese FCMD families, including 35 families whose children were diagnosed as FCMD with the typical phenotype, 12 families with a mild phenotype, and 9 families with a severe phenotype. Of the 12 propositi with the mild phenotype, 8 could walk and the other 4 could stand with support; 10 cases were homozygous for the ancestral founder (A-F) haplotype whereas the other 2 were heterozygous for the haplotype. In the 9 severe cases, who had never acquired head control or the ability to sit without support, 3 had progressive hydrocephalus, 2 required a shunt operation, and 7 had ophthalmological abnormalities. Haplotype analysis showed that 8 of the 9 cases of the severe phenotype are heterozygous for the A-F haplotype, and the other one homozygous for the haplotype. We confirmed that at least one chromosome in each of the 56 FCMD patients has the A-F haplotype. The rate of heterozygosity for the A-F haplotypes was significantly higher in severe cases than in typical or mild cases (P < 0.005). Severe FCMD patients appeared to be compound heterozygotes for the founder mutation and another mutation. Thus, the present study yielded molecular genetic evidence of a broad clinical spectrum in FCMD.

Brain↗