Browsing by Author "Meins, M."

In the present study, we present a novel reciprocal translocation t(2;20)(p24.1;q13.1) and its segregation in a three generation family. The rate of miscarriages (50%) in pregnancies from male translocation carriers Could be explained by unbalanced translocation-bearing spermatozoa found with a frequency of approximately 55% in the entire sperm population of a t(2;20)(p24.1;q13.1) carrier. These imbalanced spermatozoa mainly present as 2, der(20) and der(2), 20 missegregated (approximately 46%) while adjacent 2 and 3:1 segregation patterns account for approximately 5% and 4% of imbalances, respectively. While the translocation is associated clearly with an increased risk of early abortions (7/12) in both male and female carriers, no malformed livebirths were observed. Our results suggest complete embryonic lethality of imbalanced offspring. With respect to a high rate of segregation to 2, der(20) and to der(2), 20 imbalanced spermatozoa in male translocation carriers and with respect to known cases of partial trisomy 2p and 20q we consider that their corresponding monosomies result in fetal loss. This is the First study reporting multiple abortions associated with partial monosomy 20q13.1 --> qter and 2pter --> p24.1 and the First report on the frequency of chromosomal imbalances in gametes of a male t(2;20)(p24.1;q13.1) heterozygote. Copyright (C) 2002 S. Karger AG, Basel.

The recent discovery of heterozygous de novo mutations in the glial fibrillary acidic protein (GFAP) gene as the cause of infantile and juvenile Alexander disease has shed new light on the long-standing debate whether the adult subtype has the same etiology as infantile and juvenile Alexander disease. A 40-year-old man presented with subacute left hemiplegia and ataxia. Cranial MRI revealed disseminated patchy white matter changes involving the corpus callosum, basal ganglia and brainstem. CSF investigation demonstrated elevated total protein but was otherwise normal. Mutation analysis of the GFAP gene was performed in the patient, his mother and healthy brother. A novel heterozygous mutation in exon 4, 681G-->C, predicting an amino acid substitution E223Q in the rod region of GFAP was detected in the patient and his mother but not in his healthy brother or 150 control chromosomes. We conclude that the patient is actually afflicted with Alexander disease. Mutation analysis of GFAP should be considered in patients with remitting neurological deficits, disseminated white matter lesions and absence of inflammatory CSF changes. Copyright (C) 2003 S. Karger AG, Basel.

Isopseudodicentric chromosome 18 is very rare and results in a combination of partial trisomy and partial monosomy of chromosome 18. We report here a hypotrophic newborn with a lateral cleft lip and palate and multiple craniofacial dysmorphisms, a combined heart defect, unilateral hypoplasia of the kidney, bilateral aplasia of thumbs, and generalized contractures. Cytogenetic analysis revealed an iso-pseudodicentric chromosome 18 with breakpoint in 18q (46,XX,psu idic(18)(pter --> q22.1::q22.1 pter)). The iso-pseudodicentric chromosome 18 was observed in 100% of blood lymphocytes and umbilical cord fibroblasts, thus indicating a non-mosaic finding of the isopseudodi-centric chromosome in the child. An elongated derivative chromosome 18 had also been found prenatally in amniotic cells. In contrast, a terminal deletion (18q-) was detect-ed in placental cell cultures. The breakpoint was mapped to a 0.9 Mb region on 18q22.1 (located 64.8-65.7 Mb from the telomere of the p-arm) by a novel quantitative PCR approach with SYBR green detection. The results indicate an identical breakpoint of the isopseudodicentric chromosome 18 in the child and the 18q- chromosome in the placenta. To our knowledge this is the first report that a fetus carrying an isopseudodicentric chromosome 18 with breakpoint in 18q (46,XX,psu idic(18)(pter --> q22.1::q22.1 --> pter)) in non-mosaic form can be viable, but is associated with severe congenital malformations of the child. (C) 2003 Wiley-Liss, Inc.

RNA-binding proteins are involved in post-transcriptional processes like mRNA stabilization, post-transcriptional modification, and transport and have been suggested to play an important role in developmental gene regulation. We report here the cloning and characterization of Brunol4, a novel mouse cDNA closely related to the elav-type family of genes encoding for RNA-binding proteins and a subfamily recently named after the bruno gene of Drosophila. Murine BrunoN is localized near the centromere of chromosome 18. The cDNA sequence of Brunol4 is separated by 12 introns and the size of Brunol4 may be around 250 kb due to the large size of several introns. Brunol4 expression is detectable in the developing embryo and, later on becomes mainly restricted to cerebral structures, in particular the cerebellum where it persists in the adult organism. We predict a role of Brunol4 and the respective human homologue in differentiation and maintenance of neuronal structures. Copyright (C) 2002 S. Karger AG, Basel.

Alexander disease (AD) is a rare disorder of cerebral white matter due to a dysfunction of astrocytes. The most common infantile form presents as a megalencephalic leukodystrophy. Recently, heterozygous de novo mutations in the glial fibrillary acidic protein gene (GFAP) have been demonstrated to be associated with AD. We report heterozygous mutations in GFAP in 5 patients, including a pair of monozygotic twins, with clinical and neuroradiological features of infantile AD. Novel mutations were detected affecting nucleotides 304T --> C (L97P) and 730G --> C (R239 P) in two other patients. None of the parents of our patients carried the mutations stressing dominant de novo mutations as the cause of AD. The presence of an identical mutation 250 G --> A (R79 H) in both monozygotic twins with infantile AD points to the origin of these GFAP mutations in germ cells or very early postzygotic stages.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that apparently is lethal in male embryos. RTT almost exclusively affects female offspring and, in 99.5% of all cases, is sporadic and due to de novo mutations in the MECP2 gene. Familial cases of RTT are rare and are due to X-chromosomal inheritance from a carrier mother. We analyzed the parental origin of MECP2 mutations in sporadic cases of RTT, by analysis of linkage between the mutation in the MECP2 gene and intronic polymorphisms in 27 families with 15 different mutations, and we found a high predominance of mutations of paternal origin in 26 of 27 cases (P < .001). The paternal origin was independent of type of mutation and was found for single-base exchanges as well as for deletions. Parents were not of especially advanced age. We conclude that de novo mutations in RTT occur almost exclusively on the paternally derived X chromosome and that this is most probably the cause for the high female: male ratio observed in patients with RTT. Affected males recently have been described in a few cases of familial inheritance. Identification of the parental origin may be useful to distinguish between the sporadic form of RTT and a potentially familial form. This distinction will allow geneticists to offer more-specific counseling and discriminate between higher (maternal origin) and lower (paternal origin) recurrence risk.

Mutations in the MECP2 (Methyl-CpG-binding protein) gene recently have been reported to cause Rett syndrome (RTT), an X-linked dominant neurodevelopmental disease. We investigated 125 sporadic cases of Rett syndrome by direct sequencing. Thirty different mutations were found in 97 patients with Rett syndrome. Seventeen mutations have not been described previously. We provide evidence for the existence of several hot spot regions and of a deletion-prone region located at the 3' most region of the gene. This latter region most probably forms secondary structures in vitro. Similar structures in vivo could explain the high frequency of deletions in this region. Nine of 10 recurrent mutations were located in either the methyl CpG binding domain (MBD) or in the transcriptional regression domain (TRD), and all missense mutations were located in one of these functionally important domains. There was a high frequency of more than 60% of truncating mutations (nonsense mutations along with frameshift mutations). One patient with a mild form of the disease and a normal head growth carries a novel c.27-6C>A mutation that causes a cryptic splice site in intron I resulting in a frameshift transcript. The detection rate in our collective was 77.6%. Our findings show that the majority of German Rett patients carry mutations in the MECP2 gene confirming the suggested locus homogeneity for the disease. Hum Mutat 17:183-190, 2001, (C) 2001 Wiley Liss, Inc.