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Biomedical subjects

B Rautenstrauss

Publications and source records attributed to B Rautenstrauss.

At least 19 recordsLinked to original sources
PubMed2005

Novel EGR2 mutation R359Q is associated with CMT type 1 and progressive scoliosis.

Mutations in the early growth response 2 gene (EGR2) cause demyelinating neuropathies differing in severity and age of onset. We tested 46 unrelated Czech patients with dominant or sporadic demyelinating CMT neuropathy for mutations in the EGR2 gene. One novel de-novo mutation (Arg359Gln, R359Q) was identified in heterozygous state in a patient with a typical CMT1 phenotype, progressive moderate thoracolumbar scoliosis and without clinical signs of cranial nerve dysfunction. This patient is presently less affected compared to previously described Dejerine-Sottas neuropathy (DSN) patients carrying another substitution at codon 359 (Arg359Trp, R359W). This report shows that EGR2 mutations are rare in Czech patients with demyelinating type of CMT and suggests that different substitutions at codon 359 of EGR2 can cause significantly different phenotypes.

Adolescent↗
PubMed2004

Hearing loss as the first feature of late-onset axonal CMT disease due to a novel P0 mutation.

A Czech family with three individuals carrying a novel mutation, 290 A-->T (Glu97Val), in the myelin protein zero gene (P0) is reported. The two eldest carriers developed progressive sensorineural hearing loss and abnormal pupillary reaction at age 18. These preceded the onset of the classic signs of Charcot-Marie-Tooth disease (CMT) by more than a decade. Sural nerve biopsy and nerve conduction studies were compatible with the axonal type of CMT. The authors show that progressive hearing loss can be the first symptom in P0 mutation carriers.

Adult↗
PubMed2004

A polymorphic locus in the intron 16 of the human angiotensin-converting enzyme (ACE) gene is not correlated with complex regional pain syndrome I (CRPS I).

Exaggerated neurogenic inflammation has been recognized to be one reason for many CRPS symptoms. Since angiotensin-converting enzyme (ACE) is a key enzyme for the termination of neurogenic inflammation, it has been selected as a candidate gene for CRPS predisposition. A previous report of an insertion/deletion (I/D) polymorphism in intron 16 within the ACE gene implicated an increased risk to develop CRPS I associated with the D allele. However, in the present study the D allele frequency was not increased in CRPS I cases (0.51 for D allele, 0.49 for I allele). Furthermore, there was no co-segregation of any genotype (DD, ID, II) with the CRPS phenotype in 12 selected familial CRPS I cases from six CRPS I families. In conclusion, the results presented herein render this particular ACE gene polymorphism unlikely to be a predisposing factor for CRPS I.

DNA Mutational Analysis↗
PubMed2001

Early recognition of hereditary motor and sensory neuropathy type 1 can avoid life-threatening vincristine neurotoxicity.

Hereditary motor and sensory neuropathy type 1 (HMSN-1) is an autosomal dominant disorder, which is usually not associated with neoplastic diseases. The disease predisposes to severe vincristine neurotoxicity. We report a 31-year-old women with recurrent Hodgkin's lymphoma and unrecognized HMSN-1 who developed severe motor neuropathy 3 weeks after the first cycle of treatment including 2 mg of vincristine. HMSN is diagnosed in most cases retrospectively, usually suggested by the observation of foot abnormalities or family history. Recognizing early signs of HMSN, such as areflexia and pes cavus deformity, can prevent severe neurotoxicity of polychemotherapy by avoiding vincristine.

Adult↗
PubMed2001

Transcriptional startpoints and methylation patterns in the PMP22 promoters of peripheral nerve, leukocytes and tumor cell lines.

PMP22 is a dosage sensitive gene responsible for Charcot-Marie-Tooth type 1A (CMT1A) neuropathy and hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is expressed in myelinating Schwann cells in the peripheral nerve, but also in a variety of other tissues. PMP22 expression is regulated by alternatively used promoters, the relative expression of the different PMP22 transcripts is tissue-specific. At first we analysed the transcriptional startpoints of the different PMP22 transcripts. Transcript 1A starts from a distinct nucleotide, whereas transcript 1B and the here described transcript 1C revealed multiple transcriptional startpoints in sciatic nerve as well as in the osteosarcoma and glioblastoma cell lines, RH30 and SF763. Using promoter specific primers we identified transcripts from each of the three promoters in sciatic nerve and RH30, whereas transcript 1B is absent in SF763. Leukocytes do not express PMP22 at all. Additionally, we determined the methylation pattern of CpG islands present in the PMP22 promoters 1B and 1C for leukocytes, sciatic nerve, SF763 and RH30, the latter carrying multiple copies of the PMP22 gene. We observed that there was no methylation in promoter 1B and 1C in sciatic nerve and leukocytes. However, hypermethylation of promoter 1B was discovered in SF763 and indicates a silencing effect. In RH30 most copies of promoters 1B and 1C were methylated but the few remaining hypomethylated copies were sufficient for strong expression of PMP22. These results indicate that the transcriptional control in tumor cell lines is probably different from leukocytes and sciatic nerve.

Base Sequence↗
PubMed2000

A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3.

Autosomal recessive Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of disorders affecting the peripheral nervous system. The axonal form of the disease is designated as "CMT type 2" (CMT2), and one locus (1q21.2-q21.3) has been reported for the autosomal recessive form. Here we report the results of a genomewide search in an inbred Costa Rican family (CR-1) affected with autosomal recessive CMT2. By analyzing three branches of the family we detected linkage to the 19q13.3 region, and subsequent homozygosity mapping defined shared haplotypes between markers D19S902 and D19S907 in a 5.5-cM range. A maximum two-point LOD score of 9.08 was obtained for marker D19S867, at a recombination fraction of.00, which strongly supports linkage to this locus. The epithelial membrane protein 3 gene, encoding a PMP22 homologous protein and located on 19q13.3, was ruled out as being responsible for this form of CMT. The age at onset of chronic symmetric sensory-motor polyneuropathy was 28-42 years (mean 33.8 years); the electrophysiological data clearly reflect an axonal degenerative process. The phenotype and locus are different from those of demyelinating CMT4F, recently mapped to 19q13.1-13.3; hence, the disease affecting the Costa Rican family constitutes an axonal, autosomal recessive CMT subtype (ARCMT2B).

Adult↗
PubMed2000

PMP22 Thr118Met is not a clinically relevant CMT1 marker.

It is controversial if peripheral myelin protein 22 gene (PMP22) Thr118Met represents a functionally irrelevant polymorphism or, since hemizygosity for this variant has been found in two patients with Charcot-Marie-Tooth disease type 1 (CMT1 patients), it can act as a recessive CMT1 mutation. To shed further light on this variant and its diagnostic value we searched for carriers in 1018 individuals from the German general population, in 104 probands with hereditary neuropathy with liability to pressure palsies (HNPP) who were carriers of the 1.5-Mb deletion frequently associated with this disorder, in 187 patients with the 1.5-Mb duplication, and in 22 patients with a CMT1 phenotype who did not have any detectable anomaly in the PMP22 gene. Using allele-specific PCR we identified 14 [allele frequency (AF)=0.007] in the German general population, one (AF=0.01) in the HNPP group and six (AF=0.016) and two (AF=0.05) carriers of the PMP22 Thr118Met mutation in the CMT1 groups with and without gene defect. Carriers from all groups showed nerve conduction velocities which did not differ from typical values for these groups. We conclude that the hemizygous occurrence of the 118Met allele does not usually cause CMT1. Because of previous reports on its association with disease, and because its allele product shows abnormalities in in vitro expression systems, it seems possible that this mutation, together with yet unidentified factors, predisposes to CMT1. Alternatively, previously reported disease associations occurred by chance, and the 118Met allele causes biochemical abnormalities irrelevant for CMT1 formation. In either case this mutation is not a clinically relevant disease marker.

Biomarkers↗
PubMed2000

Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP): reliable detection of the CMT1A duplication and HNPP deletion using 8 microsatellite markers in 2 multiplex PCRs.

Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsies (HNPP) are the most frequent inherited disorders of the peripheral nervous system. They are clinically and genetically heterogeneous. A submicroscopic tandem duplication of 1. 5 Mb in chromosome 17p11.2-12 comprising the PMP22 gene is found in 70.7% of autosomal dominant Charcot-Marie-Tooth type 1 (CMT1) patients. A reciprocal deletion is found in 87.6% of HNPP patients. The size of the typical CMT1A duplication is too small for classical cytogenetics and the whole region including the CMT1A-REP elements is sometimes too complex for a single DNA analysis method. We present results of a multiplex PCR of 8 microsatellite markers with multicolour fluorescence primer labelling followed by fragment analysis on an ABI 310 Prism analyzer to simplify the diagnostic procedure. Results for 24 patients can be obtained within 24 h. This method was applied on 92 DNA samples of unrelated patients carrying a typical CMT1A duplication previously confirmed by two colour fluorescence in situ hybridization (FISH, probe c132G8) and EcoRI/SacI Southern blotting (probe pLR7.8). Three alleles of three different sizes were clearly detected at least once in 88 of them (95.6%). Subsequently this analysis was applied on 312 Czech patients and revealed a CMT1A/HNPP rearrangement in 109 out of them.

Alleles↗
PubMed1999

Expression analysis of the PMP22 gene in glioma and osteogenic sarcoma cell lines.

Previously we reported the amplification of the peripheral myelin protein 22 (PMP22) gene in cell lines of human osteogenic and glioma tumors. PMP22 normally is expressed at high levels in Schwann cells of the peripheral nervous system and is suggested to function as a structural protein of the myelin sheath. One of the most common inherited peripheral neuropathies, Charcot-Marie-Tooth Type 1A (CMT1A), is associated with a duplication of a 1.5-Mb DNA region on chromosome 17p11.2 - p12 containing PMP22. On the other hand, PMP22 is identical to gas3, whose expression is induced in growth-arresting NIH3T3-fibroblasts and is thought to play a role in cell proliferation. The precise role of gas3/PMP22 remains to be determined. Here we show that in the tumor cell lines RH30 and SF763 the amplified region including PMP22 comprises the whole 1.5-Mb CMT1A region. We could prove expression of PMP22 by reverse transcriptase-polymerase chain reaction (RT-PCR) and discovered an unusual PMP22 transcript in these tumor cell lines. Western blot analyses resulted in detection of a 22-kDa protein by the PMP22-specific antibody 558/2 and in exclusion of myelin protein zero (MPZ) expression in these cell lines.

Amino Acid Sequence↗
PubMed1999

Molecular genetics and biology of inherited peripheral neuropathies: a fast-moving field.

The recent progress of molecular genetics has considerably increased our knowledge about the underlying disease mechanism of inherited peripheral neuropathies. Mutations in three genes coding for the myelin proteins peripheral myelin protein 22, myelin protein zero and connexin 32 and in one gene coding for the transcription factor early growth response 2 element are associated with Charcot-Marie-Tooth type 1 and 2, hereditary neuropathy with liability to pressure palsies, Dejerine-Sottas syndrome and congenital hypomyelination. This review focuses on the correlation of the different human phenotypes associated with distinct mutations with those found in cellular and animal models.

Hereditary Sensory and Motor Neuropathy↗
PubMed1999

A GLC1A gene Gln368Stop mutation in a patient with normal-tension open-angle glaucoma.

PURPOSE: To present a case involving a patient with normal-tension glaucoma with a Gln368Stop mutation of the myocilin/trabecular meshwork inducible glucocorticoid response protein (MYOC/TIGR) gene. METHODS: Slit-lamp biomicroscopic and gonioscopic examination, morphometry of the optic disc, 24-hour intraocular pressure (IOP) profile, and perimetry were performed to determine the phenotype of the patient. Neurologic examination and a computed tomographic (CT) scan of the brain were performed to rule out a neurologic disorder. Single-strand confirmation polymorphism (SSCP) analysis and subsequent sequence analysis of blood was performed for genotyping of the GLC1A gene. RESULTS: A nonsense codon, namely a Gln368Stop mutation in the third exon of the GLC1A gene, was found in this patient with normal-tension glaucoma. CONCLUSION: In contrast to previous reports, a Gln368Stop mutation of the GLC1A gene need not be confined to patients with glaucomatous optic atrophy due to high IOP. The pathogenesis of glaucoma associated with GLC1A gene mutations might be more complex than expected, and (unknown) suppressor mechanisms have to be considered.

Adult↗
PubMed1999

Localization of mariner DNA transposons in the human genome by PRINS.

Homologous recombination occurring among misaligned repeated sequences is a significant source of the molecular rearrangements resulting in human genetic disease. Studies of the Charcot-Marie-Tooth disease locus on chromosome 17 have implicated the involvement of an ancient DNA transposon of the mariner family (Hsmar2) in the initiation of double-strand break events leading to homologous recombination. In this study, the genomic locations of 109 Hsmar2 elements were determined by primed in situ labeling (PRINS) using primers designed to match the right and left inverted terminal repeats (ITRs) of the transposon. Although the resolution of the PRINS technique is approximately 400 chromosomal Giemsa bands, the data presented here provide the first large-scale mapping study of these elements, which may be involved in initiation of homologous recombination events in the human genome.

Chromosome Mapping↗