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Biomedical subjects

M Vollmer

Publications and source records attributed to M Vollmer.

At least 37 records · Page 2Linked to original sources
PubMed2000

Antenatal Bartter syndrome with sensorineural deafness: refinement of the locus on chromosome 1p31.

BACKGROUND: Recently a locus for antenatal Bartter syndrome associated with sensorineural deafness was mapped to human chromosome 1p31 in a single consanguineous Bedouin family (Brennan et al. Am J Hum Genet 1998; 62: 355-361). METHODS: By haplotype analysis we demonstrate linkage to this locus in nine consanguineous families with antenatal Bartter syndrome associated with sensorineural deafness. RESULTS: The critical interval compatible with linkage was refined to 4.0 cM by two novel recombinational events with markers D1S2661 and D1S475. CONCLUSION: We thereby confirmed this gene locus and distinguished this clinical subtype from other variants of Bartter syndrome as a new disease entity.

Bartter Syndrome↗
PubMed2000

Responses of inferior colliculus neurons to amplitude-modulated intracochlear electrical pulses in deaf cats.

Current cochlear prostheses use amplitude-modulated pulse trains to encode acoustic signals. In this study we examined the responses of inferior colliculus (IC) neurons to sinusoidal amplitude-modulated pulses and compared the maximum unmodulated pulse rate (Fmax) to which they responded with the maximum modulation frequency (maxFm) that they followed. Consistent with previous results, responses to unmodulated pulses were all low-pass functions of pulse rate. Mean Fmax to unmodulated pulses was 104 pulses per second (pps) and modal Fmax was 60 pps. Above Fmax IC neurons ceased responding except for an onset burst at the beginning of the stimulus. However, IC neurons responded to much higher pulse rates when these pulses were amplitude modulated; 74% were relatively insensitive to carrier rate and responded to all modulated carriers including those exceeding 600 pps. In contrast, the responses of these neurons (70%) were low-pass functions of modulation frequency, and the remaining (30%) had band-pass functions with a maxFm of 42 and 34 Hz, respectively. Thus temporal resolution of IC neurons for modulated frequencies is significantly lower than that for unmodulated pulses. These two measures of temporal resolution (Fmax and maxFm) were uncorrelated (r(2) = 0.101). Several parameters influenced the amplitude and temporal structure of modulation responses including modulation depth, overall intensity and modulation-to-carrier rate ratio. We observed distortions in unit responses to amplitude-modulated signals when this ratio was 1/4 to 1/6. Since most current cochlear implant speech processors permit ratios that are significantly greater than this, severe distortion and signal degradation may occur frequently in these devices.

Animals↗
PubMed2000

A Bartter's syndrome mutation of ROMK1 exerts dominant negative effects on K(+) conductance.

Mutations in the gene encoding the renal epithelial K(+) channel ROMK1 (Kir 1.1) is one of the causes for Bartter's syndrome, an autosomal recessive disease. It results in defective renal tubular transport in the thick ascending limb of the loop of Henle that leads to hypokalemic metabolic alkalosis and loss of salt. Two novel ROMK1 mutations, L220F/A156V, have been described recently in a compound heterozygote patient demonstrating typical manifestations of Bartter's syndrome. Functional properties of these ROMK1 mutants were studied by coexpressing in Xenopus oocytes and by means of double electrode voltage clamp experiments. When both ROMK1 mutants were coexpressed no K(+) conductance could be detected. The same was found in oocytes expressing A156V-ROMK1 only or coexpressing wild type (wt) ROMK1 together with A156V-ROMK1. In contrast, K(+) conductances were indistinguishable from that of wt-ROMK1 when L220F-ROMK1 was expressed alone. Activation of protein kinase C signaling inhibited the conductance in both L220F-ROMK1 and wt-ROMK1 expressing oocytes. These effects were not seen in A156V-ROMK1 expressing oocytes. Because no further abnormalities in the properties or regulation of L220F-ROMK1 were detected, we conclude that A156V-ROMK1 has a dominant negative effect on L220F-ROMK1 thereby causing Bartter's syndrome type two in this patient.

Bartter Syndrome↗
PubMed1999

Hereditary isolated renal magnesium loss maps to chromosome 11q23.

Hypomagnesemia due to isolated renal magnesium loss has previously been demonstrated in two presumably unrelated Dutch families with autosomal dominant mode of inheritance. Patients with magnesium deficiency may suffer from tetany and convulsions, but the patients with hereditary renal magnesium wasting can also be clinically nonsymptomatic. In a genomewide linkage study, we first excluded a possible candidate region, on chromosome 9q, that encompasses the gene for intestinal hypomagnesemia with secondary hypocalcemia and, subsequently, found linkage to markers on chromosome 11q23. Detailed haplotype analyses identified a common haplotype segregating in both families, suggesting both their relationship through a common ancestor and the existence of a single, hypomagnesemia-causing mutation within them. The maximum two-point LOD score (Zmax) was found for marker D11S4127 (Zmax=6.41 at a recombination fraction of. 00), whereas a multipoint analysis gave a Zmax of 8.24 between markers D11S4142 and D11S4171. Key recombination events define a 5. 6-cM region between these two markers on chromosome 11q23. We conclude that this region encompasses a gene, involved in renal magnesium handling, that is mutated in our patients and is different from the gene involved in intestinal magnesium handling.

Adolescent↗
PubMed1999

Exclusion of the candidate genes ACE and Bcl-2 for six families with nephronophthisis not linked to the NPH1 locus.

BACKGROUND: Nephronophthisis (NPH) is an autosomal recessively transmitted kidney disease, characterized by cyst formation at the cortico-medullary junction, and a sclerosing tubulointerstitial nephropathy. Juvenile nephronophthisis (NPH1) is the most common genetic cause of renal failure in children and maps to chromosome 2q12-q13. The responsible gene NPHP1 has been identified and encodes for nephrocystin. Not all families with NPH demonstrate linkage to that locus. METHODS: We studied six families with NPH without linkage to the NPH1 locus. In order to attempt identification of a new causative gene, the candidate genes ACE (angiotensin converting enzyme) and Bcl-2 (B cell leukaemia/lymphoma 2 gene) originating from mouse models, were examined. For the six families highly polymorphic microsatellites covering the whole candidate gene regions were haplotyped and linkage analysis was performed. RESULTS: Haplotype analyses of all families examined were incompatible with linkage of the disease status to ACE or Bcl-2. Linkage analysis excluded both candidate gene regions with a LOD-score of < -2. CONCLUSIONS: This study excluded the candidate genes ACE and Bcl-2 for NPH. Additional linkage studies need to be performed in order to identify further genes responsible for nephronophthisis.

Adolescent↗
PubMed1999

Temporal properties of chronic cochlear electrical stimulation determine temporal resolution of neurons in cat inferior colliculus.

As cochlear implants have become increasingly successful in the rehabilitation of adults with profound hearing impairment, the number of pediatric implant subjects has increased. We have developed an animal model of congenital deafness and investigated the effect of electrical stimulus frequency on the temporal resolution of central neurons in the developing auditory system of deaf cats. Maximum following frequencies (Fmax) and response latencies of isolated single neurons to intracochlear electrical pulse trains (charge balanced, constant current biphasic pulses) were recorded in the contralateral inferior colliculus (IC) of two groups of neonatally deafened, barbiturate-anesthetized cats: animals chronically stimulated with low-frequency signals (< or = 80 Hz) and animals receiving chronic high-frequency stimulation (> or = 300 pps). The results were compared with data from unstimulated, acutely deafened and implanted adult cats with previously normal hearing (controls). Characteristic differences were seen between the temporal response properties of neurons in the external nucleus (ICX; approximately 16% of the recordings) and neurons in the central nucleus (ICC; approximately 81% of all recordings) of the IC: 1) in all three experimental groups, neurons in the ICX had significantly lower Fmax and longer response latencies than those in the ICC. 2) Chronic electrical stimulation in neonatally deafened cats altered the temporal resolution of neurons exclusively in the ICC but not in the ICX. The magnitude of this effect was dependent on the frequency of the chronic stimulation. Specifically, low-frequency signals (30 pps, 80 pps) maintained the temporal resolution of ICC neurons, whereas higher-frequency stimuli significantly improved temporal resolution of ICC neurons (i.e., higher Fmax and shorter response latencies) compared with neurons in control cats. Furthermore, Fmax and latencies to electrical stimuli were not correlated with the tonotopic gradient of the ICC, and changes in temporal resolution following chronic electrical stimulation occurred uniformly throughout the entire ICC. In all three experimental groups, increasing Fmax was correlated with shorter response latencies. The results indicate that the temporal features of the chronically applied electrical signals critically influence temporal processing of neurons in the cochleotopically organized ICC. We suggest that such plastic changes in temporal processing of central auditory neurons may contribute to the intersubject variability and gradual improvements in speech recognition performance observed in clinical studies of deaf children using cochlear implants.

Acoustic Stimulation↗
PubMed1998

Intramuscular pressure in the erector spinae and intra-abdominal pressure related to posture and load.

STUDY DESIGN: Intramuscular pressures in both Erectors Spinae and intra-abdominal pressures were measured during different holding tasks. OBJECTIVES: To investigate the potential for using intramuscular pressure measurements in both Erectors Spinae to better quantitate the role of muscles during different lifting tasks in vivo. SUMMARY OF BACKGROUND DATA: Intramuscular pressure and intra-abdominal pressure were measured previously under isometric and dynamic conditions. However, no previous study systematically has addressed the relation between intramuscular and intra-abdominal pressures and different loads, tasks, and postures. METHODS: Intramuscular and intra-abdominal were measured simultaneously with microtip pressure transducers in 10 healthy volunteers performing 24 different static holding tasks. Tasks included different weights (10 kg and 20 kg), postures (squat or back lift), and positions of the weight. RESULTS: Intramuscular pressures were dependent on posture. Kyphotic back posture produced intramuscular pressures of 120-130 mm Hg, compared with the 10-25 mm Hg produced when volunteers were in the erect position (P < 0.001). Holding a 10-kg weight at the thighs close to the body produced significantly (P < 0.001) lower intramuscular pressures (25-32 mm Hg) than that produced by holding it 25 cm in front of the body (47-56 mm Hg). In all tasks, intramuscular pressures were significantly higher with the 20-kg weight than with the 10-kg weight (P < 0.001). Highest values (> 300 mm Hg) were measured when the 20-kg weight was held in the kyphotic posture above the floor and 25 cm away from the body. CONCLUSIONS: Intramuscular pressure measurements in the erector spinae seem to be a valuable tool for quantitating the role of back muscles during different lifting tasks.

Abdomen↗
PubMed1998

Early preferential stimulation of gamma delta T cells by TNF-alpha.

Although recent findings indicate that gamma delta T cells influence both early innate and Ag-specific adaptive host responses, it has remained unclear what triggers gamma delta T cell reactivity. Investigating very early T cell activation in mouse and human models of bacterial infection, we measured CD69 expression as an indicator of early cellular activation. Both murine alpha beta and gamma delta T cells responded polyclonally to systemic bacterial infections, and to LPS. However, gamma delta T cells responded more strongly to the bacteria and to LPS. In vitro LPS-stimulated human T cells showed a similar differential response pattern. We identified TNF-alpha as mediator of the early differential T cell activation, and of differential proliferative responses. The stronger response of gamma delta T cells to TNF-alpha was correlated with higher inducible expression levels of TNF-Rp75. Among unstimulated splenocytes, more gamma delta T cells than alpha beta T cells expressed CD44 at high levels. The data suggest that TNF-Rp75 determines the differential T cell reactivity, and that most gamma delta T cells in the normal spleen are present in a presensitized state. As TNF-alpha stimulates activated T cells, it may early preferentially connect gamma delta T cell functions with those of cells that produce this cytokine, including activated innate effector cells and Ag-stimulated T lymphocytes.

Animals↗
PubMed1998

Two novel mutations of the gene for Kir 1.1 (ROMK) in neonatal Bartter syndrome.

Bartter syndrome, an autosomal recessive renal tubular disorder, is associated with hypokalemic metabolic alkalosis with high renin and aldosterone plasma concentrations with low or normal blood pressure and renal salt loss. Two genes, the gene encoding the furosemide-sensitive apical Na-K-2Cl cotransporter (NKCC2) and the gene encoding the luminal inwardly-rectifying potassium channel Kir 1.1 (ROMK), have been reported to cause the neonatal subtype of Bartter syndrome. In a patient with neonatal Bartter syndrome, we report two novel mutations resulting in amino acid exchanges Ala156Val and Leu220Phe in the gene for Kir 1.1 that have been identified by single-strand conformation polymorphism analysis and subsequent direct sequencing. Both mutations occur in functional relevant domains of the channel protein and are therefore highly suggestive of altering channel properties.

Adult↗
PubMed1998

Novel molecular variants of the Na-K-2Cl cotransporter gene are responsible for antenatal Bartter syndrome.

Antenatal Bartter syndrome is a variant of inherited renal-tubular disorders associated with hypokalemic alkalosis. This disorder typically presents as a life-threatening condition beginning in utero, with marked fetal polyuria that leads to polyhydramnios and premature delivery. Another hallmark of this variant is a marked hypercalciuria and, as a secondary consequence, the development of nephrocalcinosis and osteopenia. We have analyzed 15 probands belonging to 13 families and have performed SSCP analysis of the coding sequence and the exon-intron boundaries of the NKCC2 gene; and we report 14 novel mutations in patients with antenatal Bartter syndrome, as well as the identification of three isoforms of human NKCC2 that arise from alternative splicing.

Amino Acid Sequence↗
PubMed1998

The gene for human fibronectin glomerulopathy maps to 1q32, in the region of the regulation of complement activation gene cluster.

Fibronectin glomerulopathy (GFND) is a newly recognized autosomal dominant disease of the kidney that results in albuminuria, microscopic hematuria, hypertension, renal tubular acidosis type IV, and end-stage renal disease in the 2d to 6th decade of life. The disease is characterized histologically by massive deposits of fibronectin (Fn) present in the subendothelial spaces of renal glomerular capillaries. The cause of human GFND is unknown. In order to localize a candidate gene for GFND, we performed linkage analysis of a large, 193-member pedigree containing 13 affected individuals. Since we had previously excluded the genes for Fn and uteroglobin as candidate genes for GFND, a total-genome search for linkage was performed. Examination of 306 microsatellite markers resulted in a maximum two-point LOD score of 4.17 at a recombination fraction of. 00 for marker D1S249, and a maximum multipoint LOD score of 4.41 for neighboring marker D1S2782. By detection of recombination events, a critical genetic interval of 4.1 cM was identified, which was flanked by markers D1S2872 and D1S2891. These findings confirm that GFND is a distinct disease entity among the fibrillary glomerulopathies. Gene identification will provide insights into the molecular interactions of Fn in GFND, as well as in genetically unaltered conditions.

Adult↗
PubMed1998

Autosomal dominant medullary cystic kidney disease: evidence of gene locus heterogeneity.

Autosomal dominant medullary cystic kidney disease (ADMCKD; synonym: medullary cystic disease, MCD) is an autosomal dominant kidney disorder, sharing morphological and clinical features with recessive juvenile nephronophthisis (NPH), such as reduced urinary concentration ability and multiple renal cysts at the corticomedullary junction. While in NPH end-stage renal disease (ESRD) occurs in adolescence, ADMCKD leads to ESRD in adulthood. Recently a gene locus for ADMCKD has been localized to chromosome 1q21 in two large Cypriot families. This prompted us to examine linkage in three ADMCKD-families, using the same set of polymorphic microsatellite markers spanning the critical region on chromosome 1q21. Haplotype analysis revealed that none of the three families showed linkage to this locus, thus demonstrating evidence for genetic locus heterogeneity. Additional linkage analysis studies need to be performed in order to identify further gene loci cosegregating with this autosomal dominant kidney disorder.

Adult↗
PubMed1997

Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. APN Study Group. Arbeitsgemeinschaft für Pädiatrische Nephrologie.

Familial juvenile nephronophthisis (NPH), an autosomal recessive cystic disease of the kidney, is the most common genetic cause of end-stage renal disease (ESRD) in the first two decades of life. A gene locus for nephronophthisis type 1 (NPH1) has been mapped by linkage analysis to chromosome 2q13. We performed a haplotype analysis in 16 NPH families with at least two affected patients with the typical history, clinical signs and histology of NPH using microsatellite markers of the NPH1 genetic region. By demonstration of a recombinant event marker D2S1893 was identified as a novel centromeric flanking marker to the NPH1 critical genetic region. Absence of linkage to the NPH1 locus in six NPH families confirmed the existence of at least one additional gene locus for NPH. Linkage to the NPH1 locus was demonstrated in 10 families. In 8 of these families a homozygous deletion was identified. These data permit for the first time the study of the development of renal failure in a subset of NPH1 families, which is most likely homogeneous with regard to the responsible gene locus. We present a statistical description of serial serum creatinine measurements in NPH1. Analysis of renal death revealed a median of 13.1 years. Age-dependent quartiles were generated for serum creatinine. In summary, the new marker provides a diagnostic tool to aid in the diagnosis of NPH, while the progression charts offer a standard for an assessment of the rate of progression to ESRD for patients with NPH1 to be used in future therapeutic trials and for a prediction of the individual course of the disease.

DNA, Satellite↗
PubMed1997

A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1.

Juvenile nephronophthisis (NPH), an autosomal recessive cystic kidney disease, is the primary genetic cause of chronic renal failure in children. About two thirds of patients with NPH carry a large homozygous deletion at the gene locus NPH1 on 2q13. We here identify a novel gene. NPHP1, which extends over most of this common deletion. The 4.5-kb transcript encodes a protein with an SH3 domain, which is highly conserved throughout evolution. The 11-kb interval between the 3' end of NPHP1 and an inverted repeat containing the distal deletion breakpoint was found to contain the first exon of a second gene, MALL. In patients with a hemizygous deletion of the NPH1 region, additional point mutations were found in NPHP1 but not in MALL.

Adaptor Proteins, Signal Transducing↗
PubMed1997

A common NKCC2 mutation in Costa Rican Bartter's syndrome patients: evidence for a founder effect.

Bartter's syndrome involves an overlapping set of closely related renal tubular disorders that can be subdivided into at least three clinical phenotypes: (1) the hypercalciuric antenatal Bartter variant; (2) the classic Bartter variant; and (3) the hypocalciuric-hypomagnesemic Gitelman variant. Recent data demonstrate that in several phenotypically indistinguishable cohorts, antenatal Bartter's syndrome is genetically heterogeneous. In these patients, mutations in the genes encoding either the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) or the ATP-regulated potassium channel ROMK (KCNJI) have been identified. A cohort of 20 Costa Rican patients with a congenital syndrome that bears strong similarities to antenatal Bartter's syndrome but also has several distinct features has recently been described. In this cohort, we have identified a predominant mutation that introduces a premature stop in codon W625 of the NKCC2 gene (SCL12A1). This mutant allele is contained on a single common haplotype, suggesting that the majority of antenatal Bartter's syndrome patients in Costa Rica share a single common ancestor.

Adult↗