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Biomedical subjects

S M Tanner

Publications and source records attributed to S M Tanner.

At least 19 recordsLinked to original sources
PubMed2005

Myopathy with skeletal asymmetry and hemidiaphragm elevation is caused by myotubularin mutations.

The authors report two families with a myopathy phenotype affecting only women, marked by asymmetric weakness, skeletal asymmetry, and an elevated hemidiaphragm. One family had a mutation in a stop codon in exon 9 of the myotubularin gene, and the other had a splice site mutation in exon 13. Both families had manifesting and nonmanifesting carriers. Skewed X-inactivation appeared to explain the clinical manifestations in only one of the two families.

Adult↗
PubMed2003

X-inactivation patterns in carriers of X-linked myotubular myopathy.

X-linked myotubular myopathy is a rare severe muscle disorder in affected male neonates. Most female carriers are free from symptoms. Skewed X inactivation has been proposed to be responsible for the affected phenotype seen in some carriers. We have compared the X inactivation patterns in blood DNA with the clinical phenotype in carriers of X-linked myotubular myopathy. The X-inactivation analysis was performed using HpaII predigestion of DNA followed by polymerase chain reaction of the highly polymorphic CAG repeat of the androgen receptor (AR) gene. The frequency of skewed X inactivation was similar in the X-linked myotubular myopathy carriers (22%) and in 235 controls (18%). Three overtly affected carriers had skewed X inactivation with the mutated X as the predominantly active X in at least two of them. Four females with mild symptoms had random X inactivation. The unaffected X-linked myotubular myopathy carriers had either skewed X inactivation in favour of expression from the normal X or random X-inactivation. Thus, there was a tendency for females with a more severe phenotype to have a skewed pattern of X inactivation, while females with an intermediate phenotype had a random pattern of X-inactivation.

Adolescent↗
PubMed2001

BAALC, the human member of a novel mammalian neuroectoderm gene lineage, is implicated in hematopoiesis and acute leukemia.

The molecular basis of human leukemia is heterogeneous. Cytogenetic findings are increasingly associated with molecular abnormalities, some of which are being understood at the functional level. Specific therapies can be developed based on such knowledge. To search for new genes in the acute leukemias, we performed a representational difference analysis. We describe a human gene in chromosome 8q22.3, BAALC (brain and acute leukemia, cytoplasmic), that is highly conserved among mammals but evidently absent from lower organisms. We characterized BAALC on the genomic level and investigated its expression pattern in human and mouse, as well as its complex splicing behavior. In vitro studies of the protein showing its subcellular localization suggest a function in the cytoskeleton network. Two isoforms are specifically expressed in neuroectoderm-derived tissues, but not in tumors or cancer cell lines of nonneural tissue origin. We show that blasts from a subset of patients with acute leukemia greatly overexpress eight different BAALC transcripts, resulting in five protein isoforms. Among patients with acute myeloid leukemia, those overexpressing BAALC show distinctly poor prognosis, pointing to a key role of the BAALC products in leukemia. Our data suggest that BAALC is a gene implicated in both neuroectodermal and hematopoietic cell functions.

3T3 Cells↗
PubMed2001

Aberrant promoter methylation of previously unidentified target genes is a common abnormality in medulloblastomas--implications for tumor biology and potential clinical utility.

Medulloblastomas exhibit an array of diverse cytogenetic abnormalities. To evaluate the significance of epigenetic rather than genetic lesions in medulloblastomas and other primitive neuroectodermal tumors (PNETs) of the childhood CNS we performed a systematic analysis of gene specific and global methylation. Methylation-specific PCR detected no methylation for p15(INK4B), von Hippel Lindau and TP53 and only limited methylation for E-Cadherin and p16(INK4A) in tumors. The cell lines Daoy and MHH-PNET-5 in which the p16(INK4A) promoter was methylated did not express the gene, but demonstrated abnormalities by SSCP. Immunohistochemistry for p16 was negative in all examined normal cerebella and medulloblastomas. Using the technique of Restriction Landmark Genomic Scanning we detected methylation affecting up to 1% of all CpG islands in primary MB/PNETs and 6% in MB cell lines. Methylation patterns differed between medulloblastomas and PNETs. Examination of several methylated sequences revealed homologies to known genes and expressed sequences. Analysis of survival data identified seven of 30 hypermethylated sequences significantly correlating with poor prognosis. We suggest that DNA hypermethylation has an outstanding potential for the identification of novel tumor suppressors as well as diagnostic and therapeutic targets in MBs and other PNETs of the CNS.

Adolescent↗
PubMed2001

Expression profiling reveals fundamental biological differences in acute myeloid leukemia with isolated trisomy 8 and normal cytogenetics.

Acute myeloid leukemia (AML) is a heterogeneous group of diseases. Normal cytogenetics (CN) constitutes the single largest group, while trisomy 8 (+8) as a sole abnormality is the most frequent trisomy. How trisomy contributes to tumorigenesis is unknown. We used oligonucleotide-based DNA microarrays to study global gene expression in AML+8 patients with +8 as the sole chromosomal abnormality and AML-CN patients. CD34(+) cells purified from normal bone marrow (BM) were also analyzed as a representative heterogeneous population of stem and progenitor cells. Expression patterns of AML patients were clearly distinct from those of CD34(+) cells of normal individuals. We show that AML+8 blasts overexpress genes on chromosome 8, estimated at 32% on average, suggesting gene-dosage effects underlying AML+8. Systematic analysis by cellular function indicated up-regulation of genes involved in cell adhesion in both groups of AML compared with CD34(+) blasts from normal individuals. Perhaps most interestingly, apoptosis-regulating genes were significantly down-regulated in AML+8 compared with AML-CN. We conclude that the clinical and cytogenetic heterogeneity of AML is due to fundamental biological differences.

Acute Disease↗
PubMed2000

MTM1 mutations in X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM; MIM# 310400) is a severe congenital muscle disorder caused by mutations in the MTM1 gene. This gene encodes a dual-specificity phosphatase named myotubularin, defining a large gene family highly conserved through evolution (which includes the putative anti-phosphatase Sbf1/hMTMR5). We report 29 mutations in novel cases, including 16 mutations not described before. To date, 198 mutations have been identified in unrelated families, accounting for 133 different disease-associated mutations which are widespread throughout the gene. Most point mutations are truncating, but 26% (35/133) are missense mutations affecting residues conserved in the Drosophila ortholog and in the homologous MTMR1 gene. Three recurrent mutations affect 17% of the patients, and a total of 21 different mutations were found in several independent families. The frequency of female carriers appears higher than expected (only 17% are de novo mutations). While most truncating mutations cause the severe and early lethal phenotype, some missense mutations are associated with milder forms and prolonged survival (up to 54 years).

Alternative Splicing↗
PubMed1999

Skewed X-inactivation in a manifesting carrier of X-linked myotubular myopathy and in her non-manifesting carrier mother.

X-linked recessive myotubular myopathy (XLMTM) is a muscle disorder usually affecting newborn males. In the majority of cases, muscle weakness and hypotonia lead to a rapid demise at neonatal age. The responsible MTM1 gene is located in proximal Xq28. Heterozygous carriers are described as being asymptomatic but, in a few cases, mild facial weakness has been reported. We report a family in which a 39-year old female showed severe progressive muscle weakness. XLMTM was initially diagnosed in the male offspring of one of the patient's sisters. The patient, one of her sisters, and their mother were heterozygous carriers for a common MTM1 gene mutation. We found an extremely skewed X-inactivation pattern in the patient and, in the opposite direction, in her non-manifesting carrier mother, thus explaining her normal phenotype and indicating a possible inheritance of skewed X-inactivation. Linkage analysis excluded a possible involvement of the XIST locus at Xq13.

Adult↗
PubMed1999

Characterization of 34 novel and six known MTM1 gene mutations in 47 unrelated X-linked myotubular myopathy patients.

X-linked myotubular myopathy (XLMTM) is a congenital muscle disorder mainly affecting newborn males. Neonatal muscle weakness and hypotonia usually leads to a rapid demise. The responsible gene, MTM1, was isolated in 1996, and mutational data derived from 90 patients have been published. We report on our findings in a further 53 patients, using genomic DNA and mRNA screening protocols. Thirty-four novel mutations were identified in 37 cases, and six known mutations found in 10 other patients. The 34 new mutations include five large deletions, eight nonsense, six frameshift, five missense, and eight splice-site mutations, whereas two intronic variants causing partial exon skipping represent the first report on such a mechanism in MTM1. Two deletions, one involving exon 1, and the second exon 15, are the first defects to be identified in these exons. The heterogeneity of the mutations, their mutational origins, and the varied ethnic backgrounds of the patients, indicate that the majority of XLMTM families are affected by unique MTM1 mutations.

Adult↗
PubMed1998

Confirmation of prenatal diagnosis results of X-linked recessive myotubular myopathy by mutational screening, and description of three new mutations in the MTM1 gene.

X-linked recessive myotubular myopathy (XLMTM; MTM1) is a severe neonatal disorder often causing perinatal death of the affected males. The responsible gene, designated MTM1, was localized to proximal Xq28 and recently isolated. The characterization of MTM1 allowed us to screen for causing mutations in three families, previously investigated by linkage analysis. Using exon amplification, single strand conformation polymorphism, and subsequent sequencing analysis, three new mutations and their mutational origin were characterized by analyzing 10 exons. An acceptor splice site and a frameshift mutation were correlated with the concurrent appearance of XLMTM in two families. A third intronic mutation was also analyzed by reverse transcription PCR and revealed a cryptic splice site mutation cosegregating with the presumed XLMTM haplotype in the third family. These results further support the implication of the MTM1 gene in XLMTM and allow efficient and reliable carrier and prenatal diagnosis in these families. Direct mutational diagnosis of families at risk in combination with haplotype analysis avoid the drawbacks using only linkage analysis, make genetic counselling far more reliable, and early clinical management of this disease more appropriate. Moreover, pedigree analyses provide first information on de novo mutation frequency in this newly identified human disease gene.

DNA Mutational Analysis↗
PubMed1997

Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. ENMC International Consortium on Myotubular Myopathy. European Neuro-Muscular Center.

X-linked recessive myotubular myopathy (XLMTM) is characterized by severe hypotonia and generalized muscle weakness, with impaired maturation of muscle fibres. The gene responsible, MTM1, was identified recently by positional cloning, and encodes a protein (myotubularin) with a tyrosine phosphatase domain (PTP). Myotubularin is highly conserved through evolution and defines a new family of putative tyrosine phosphatases in man. We report the identification of MTM1 mutations in 55 of 85 independent patients screened by single-strand conformation polymorphism for all the coding sequence. Large deletions were observed in only three patients. Five point mutations were found in multiple unrelated patients, accounting for 27% of the observed mutations. The possibility of detecting mutations and determining carrier status in a disease with a high proportion of sporadic cases is of importance for genetic counselling. More than half of XLMTM mutations are expected to inactivate the putative enzymatic activity of myotubularin, either by truncation or by missense mutations affecting the predicted PTP domain. Additional mutations are missenses clustered in two regions of the protein. Most of these affect amino acids conserved in the homologous yeast and Caenorhabditis elegans proteins, thus indicating the presence of other functional domains.

Alternative Splicing↗
PubMed1995

Anabolic steroid use by adolescents: prevalence, motives, and knowledge of risks.

Athletes and nonathletes use anabolic-androgenic steroids (AAS) to improve their strength and enhance their appearance. Few studies have been undertaken in the 1990s to assess the use of AAS in adolescents, following changes in legislation. This study was conducted to determine the prevalence of AAS use by high school students in Denver, Colorado, an area with high sports participation. A confidential questionnaire was completed by 6,930 students (response rate 96.6%) at 10 Denver high schools. The prevalence of AAS use was 2.7% (4.0% for boys and 1.3% for girls). Prevalence was slightly higher in sport participants than nonparticipants. The mean age of starting AAS was 14 years (range 8-17 years). This study is the first documented detailed assessment of high school students' knowledge of the risks of AAS. It shows knowledge deficits regarding potential side effects. Users of AAS were less likely than nonusers to acknowledge the risks of AAS. Only 18% of students claim to have been informed about AAS by physicians. The results suggest that health care providers should provide more information to adolescents about AAS. If educational efforts are found effective, teaching efforts regarding AAS should start in junior high school or sooner and continue through high school.

Adolescent↗
PubMed1994

Preparticipation examination targeted for the female athlete.

The preparticipation examination is an ideal opportunity for health care professionals to enhance the safety of sports competition for girls and women. Assessing and providing education about conditioning, body composition, nutrition, musculoskeletal rehabilitation, and health maintenance may foster healthy sports participation in the female athlete.

Adolescent↗
PubMed1985

Insulin resistance in total lipodystrophy: evidence for a pre-receptor defect in insulin action.

The cause of insulin resistance in lipodystrophic diabetes is unknown but has generally been ascribed to dysfunction at either the receptor or post receptor level. In a 14 year-old girl with total acquired lipodystrophy, subcutaneous and intravenous insulin requirements approximated 600 units daily. However, circulating total and free insulin levels were not increased, and during testing by the euglycemic clamp method, the glucose response to increasing free insulin concentrations was within the range found in eight subjects with insulin-dependent diabetes. Insulin clearance during the euglycemic clamp was 43, 98, 115, and 116 mL/kg/min at each of four insulin infusion rates compared to means of 13, 13, 12, and 11 in the control subjects with diabetes. No detectable degrading activity was present in serum, and serum inhibited insulin degradation normally. Binding of insulin to IgG, IgM, and IgE was not increased, insulin binding to monocytes and erythrocytes was not sufficiently abnormal to account for the the insulin resistance, and insulin receptor increased insulin clearance or accelerated degradation of insulin by tissues.

Adolescent↗
PubMed1983

Hamartoma of CNS associated with precocious puberty.

A male infant had precocious puberty and hamartoma of the CNS. Signs of puberty appeared and progressed from 6 months of age. A computed tomographic scan disclosed an interpedunculary tumor. A craniotomy was successfully performed at 11/2 years of age, and 90% of the tumor was removed. Histologically, the tissue was identified as a hypothalamic hamartoma. Pubertal development stopped. The patient is now 4 years 9 months old and well. Review of medical literature covering a span of 47 years showed 50 cases of hamartomas in or near the hypothalamus confirmed by surgical exploration or autopsy. The male-female ratio of hamartomas with precocious puberty derived from these data is 2:1. Convulsions, mental retardation, or behavioral disorders were present in 48% of the cases; 36% had precocious puberty.

Brain Neoplasms↗
PubMed1982

A new test of peripheral insulin sensitivity in vivo using artificial beta cell.

A new in vivo test of insulin sensitivity is described. It utilizes closed-loop insulin delivery device (GCIIS, Biostator) capable of infusing glucose and insulin according to preselected algorithms. In euglycemic patients, insulin was infused by GCIIS to maintain euglycemia in the face of challenges with gradually increasing doses on intravenously administered glucose. Under the described experimental conditions, the endogenous insulin release was minimized as evidenced by serum C-peptide levels of less than 2 ng/ml, and thus the peripheral disposal of glucose should have depended entirely on the exogenous insulin. The amount of the insulin infused was considered to be a measure of peripheral insulin sensitivity. The test was applied to normal and non diabetic obese individuals, and to diabetics, both insulin dependent and independent. Significant insulin resistance was demonstrated in the obese and diabetic patients. In two obese females, the test was repeated after a prolonged period of starvation, and showed marked increase in insulin sensitivity. In two poorly controlled insulin dependent diabetics, marked increase in insulin sensitivity was also observed, here following a prolonged period of euglycemia (48 hours). It is concluded that the GCIIS controlled insulin sensitivity test is a simple, reliable test of peripheral insulin sensitivity, most convenient for clinical and experimental studies in vivo.

Adult↗
PubMed1982

Use of a glucose-controlled insulin infusion system in children and adolescents with insulin-dependent diabetes.

Seven children and adolescents (aged 8 to 23 years, mean 16 years) with poorly controlled insulin-dependent diabetes mellitus were evaluated with a glucose-controlled insulin infusion system (GCIIS) to determine whether its use could help define appropriate long-term insulin treatment regimens and increase patient understanding and compliance with such regimens. The GCIIS-derived insulin regimen was characterized by a mean insulin requirement of 1.0 +/- 0.1 units/kg/day, with 55% of the total insulin dose given in the morning and 45% in the evening. Forty-eight percent of the total insulin was short acting. Both clinical and biochemical indices of metabolic control (HbA1c levels) improved after insulin dose readjustment based on GCIIS data. The continuous documentation of blood glucose levels provided by the GCIIS was valuable in educating patients about the interrelationship between insulin, exercise, and diet. Using GCIIS data, patients were taught to apply the new regimen flexibly to variations in activity and diet. Thus, the GCIIS can aid in the management of selected children and adolescents with insulin-dependent diabetes millitus. Insulin patterns derived from its use suggest that a flexible, twice daily regimen characterized by nearly equal proportions of short- and intermediate-acting preparations may be beneficial for other pediatric patients.

Adolescent↗