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K Zerres

Publications and source records attributed to K Zerres.

At least 91 records · Page 5Linked to original sources
PubMed1997

De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling.

Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder. We have identified de novo rearrangements in 7 (approximately 2%) index patients from 340 informative SMA families. In each, the rearrangements resulted in the absence of the telomeric copy of the survival motor neuron (SMN) gene (telSMN), in two cases accompanied by the loss of the neuronal apoptosis-inhibitory protein gene . Haplotype analysis revealed unequal recombination in four cases, with loss of markers Ag1-CA and C212, which are near the 5' ends of the SMN genes. In one case, an interchromosomal rearrangement involving both the SMN genes and a regrouping of Ag1-CA and C212 alleles must have occurred, suggesting either interchromosomal gene conversion or double recombination. In two cases, no such rearrangement was observed, but loss of telSMN plus Ag1-CA and C212 alleles in one case suggested intrachromosomal deletion or gene conversion. In six of the seven cases, the de novo rearrangement had occurred during paternal meiosis. Direct detection of de novo SMA mutations by molecular genetic means has allowed us to estimate for the first time the mutation rate for a recessive disorder in humans. The sex-averaged rate of 1.1 x 10(-4), arrived at in a proband-based approach, compares well with the rate of 0.9 x 10(-4) expected under a mutation-selection equilibrium for SMA. These findings have important implications for genetic counseling and prenatal diagnosis in that they emphasize the relevance of indirect genotype analysis in combination with direct SMN-gene deletion testing in SMA families.

Alleles↗
PubMed1997

Identification of mutations in the duplicated region of the polycystic kidney disease 1 gene (PKD1) by a novel approach.

Mutation screening of the major autosomal dominant polycystic kidney disease gene (PKD1) has been complicated by the large transcript size (> 14 kb) and by reiteration of the genomic area encoding 75% of the protein on the same chromosome (the HG loci). The sequence similarity between the PKD1 and HG regions has precluded specific analysis of the duplicated region of PKD1, and consequently all previously described mutations map to the unique 3' region of PKD1. We have now developed a novel anchored reverse-transcription-PCR (RT-PCR) approach to specifically amplify duplicated regions of PKD1, employing one primer situated within the single-copy region and one within the reiterated area. This strategy has been incorporated in a mutation screen of 100 patients for more than half of the PKD1 exons (exons 22-46; 37% of the coding region), including 11 (exons 22-32) within the duplicated gene region, by use of the protein-truncation test (PTT). Sixty of these patients also were screened for missense changes, by use of the nonisotopic RNase cleavage assay (NIRCA), in exons 23-36. Eleven mutations have been identified, six within the duplicated region, and these consist of three stop mutations, three frameshifting deletions of a single nucleotide, two splicing defects, and three possible missense changes. Each mutation was detected in just one family (although one has been described elsewhere); no mutation hot spot was identified. The nature and distribution of mutations, plus the lack of a clear phenotype/genotype correlation, suggest that they may inactivate the molecule. RT-PCR/PTT proved to be a rapid and efficient method to detect PKD1 mutations (differentiating pathogenic changes from polymorphisms), and we recommend this procedure as a firstpass mutation screen in this disorder.

Adult↗
PubMed1997

Missense mutations in exon 6 of the survival motor neuron gene in patients with spinal muscular atrophy (SMA).

Spinal muscular atrophy (SMA) is a frequent autosomal recessive neurodegenerative disorder leading to weakness and atrophy of voluntary muscles. The survival motor neuron gene (SMN) is a strong candidate for SMA and present in two highly homologous copies (telSMN and cenSMN) within the SMA region (5q11.2-q13.3). More than 90% of SMA patients show homozygous deletions of at least exon 7 of telSMN, whereas absence of cenSMN seems to have no clinical consequences. In 23 non-deleted SMA patients, we searched for intragenic mutations of the SMN genes in exons 1-7 and the promotor region by single strand conformation analysis. We identified two different missense mutations, S2621 and T2741, in exon 6 of telSMN in three independent SMA families, providing further evidence for the telSMN gene as a SMA determining gene. Both mutations, as well as two previously described mutations (Y272C and G279V) are located within a highly conserved interval from codon 258 to codon 279 which seems to be an important functional domain of the telSMN protein. Recently, this region has been shown to contain a tyrosine/glycine-rich motif, which is also present in various RNA binding proteins, suggesting a potential role of SMN in RNA metabolism. Missense mutations might be useful for in vivo and transgenic experiments and further investigations on understanding the function of the telSMN protein.

Adolescent↗
PubMed1997

Proximal and distal spinal muscular atrophy in one family: molecular genetic studies provide further evidence for the non-allelic origin of both diseases.

We present the results of clinical and molecular genetic investigations of a family in which the father suffers from distal spinal muscular atrophy and the younger son is affected by infantile autosomal recessive SMA type I. The molecular analysis of the SMN gene showed homozygous deletions of telSMN exons 7 and 8 in the son only. This was probably the result of a new mutation in the paternal haplotype, since the affected boy did not inherit one copy of the marker Ag1-CA. These results indicate that distal and proximal SMA in this family are not caused by the same gene on chromosome 5q.

Adult↗
PubMed1996

Craniometaphyseal dysplasia as a rare cause of a severe neonatal nasal obstruction.

We report on a 2-year-9-month-old boy with the typical features of craniometaphyseal dysplasia with hyperostosis and sclerosis of the cranial vault and mild splaying of the metaphyses. The boy already presented during the neonatal period with the unusual clinical picture of breathing and feeding problems due to severely enlarged and ossified inferior nasal conchae causing obstruction of the nasal lumen.

Age of Onset↗
PubMed1996

Clinical spectrum and diagnostic criteria of infantile spinal muscular atrophy: further delineation on the basis of SMN gene deletion findings.

With the evidence of deletions in the region responsible for autosomal recessive spinal muscular atrophy (SMA) on chromosome 5, it is now possible to further clarify the clinical and diagnostic findings in proximal SMA. Homozygous deletions of the survival motor neuron (SMN) gene can be detected in about 95% of patients with early onset SMA. In a series of more than 200 patients, we tested 31 patients with atypical features of SMA who fulfilled at least one exclusion criterion according to the diagnostic criteria of the International SMA Consortium for the presence of SMN gene deletions. The patients were subdivided into two groups: 1. Seven index patients being not deleted for the SMN gene who belonged to a well-defined SMA plus variant that has already been shown to be unlinked with chromosome 5q markers: diaphragmatic SMA, SMA plus olivopontocerebellar hypoplasia, SMA with congenital arthrogryposis and bone fractures. 2. Twenty-four patients with clinical signs of SMA and neurogenic findings in EMG/muscle biopsy who had unusual features or other organ involvement. In order to structure this heterogeneous group, each patient was assigned to a subgroup according to the leading atypical feature. In 5 out of 8 unrelated patients with a history of preterm birth and/or perinatal asphyxia leading to a picture of severe SMA in combination with respiratory distress and/or cerebral palsy, no deletion of the SMN gene could be detected. There were five unrelated patients with extended central nervous system involvement (cerebral atrophy, EEG abnormalities, pyramidal tract signs, evidence of cerebellar involvement). Most of these patients (4/5) proved to belong to SMA 5q on the basis of SMN gene deletion findings. The same applied to a group of three patients with classical SMA in association with congenital malformations (mainly heart defect). A fourth group of three patients was characterized mainly by an unusual improvement of the condition; in these patients no SMN gene deletions were present. In three index patients a more complex syndrome of the CNS and other organs was suggested, but the detection of SMN gene deletions in two of them made a coincidence of features more likely. In addition, SMN gene deletions were found in two patients with evidence of congenital fibre type dysproportion in one and extremely raised CK activity ( > 10fold) in the other. While the confirmation of SMN gene deletions is very useful in cases with diagnostic doubts, caution is required when offering prenatal prediction with regard to SMA 5q in families with atypical features. There is strong evidence that there are clinical entities resembling SMA which most likely have another pathogenetic background.

Arthrogryposis↗
PubMed1996

Autosomal recessive polycystic kidney disease.

Autosomal recessive polycystic kidney disease (ARPKD) is a rare inherited disorder which usually becomes clinically manifest in early childhood. With increasing knowledge and improving diagnostic techniques it has become evident that the spectrum of ARPKD is much more variable than was previously thought. Presentation of ARPKD at later ages and survival into adulthood is well known. Diagnostic criteria, clinical course, genetics and differential diagnosis of ARPKD are presented.

Chromosome Mapping↗
PubMed1996

Autosomal recessive polycystic kidney disease in 115 children: clinical presentation, course and influence of gender. Arbeitsgemeinschaft für Pädiatrische, Nephrologie.

The clinical course of 66 boys and 49 girls with autosomal recessive polycystic kidney disease recruited from departments of paediatric nephrology was investigated over a mean observation period of 4.92 years. This is a selected study group of children from departments of paediatric nephrology who in most cases survived the neonatal period, since birth clinics did not participate. The median age at diagnosis was 29 days (prenatal to 14.5 years). We observed decreased glomerular filtration rates (GFRs) in 72% (median age at onset of decrease of GFR < 2 SD, 0.6 years; range, 0-18.7 years), and 11 patients developed end-stage renal disease. Hypertension requiring drug treatment was found in 70% (median age at start of medication, 0.5 years; range, 0-16.7 years). Kidney length was above the 97th centile in 68% of patients, and kidney length did not increase with age or deterioration of renal function. Urinary tract infections occurred in 30%, growth retardation in 25%, and clinical signs of hepatic fibrosis were detected in 46%. Thirteen patients (11%) died during the observation period, 10 of them in the first year of life. There was a statistically significant sex difference in terms of a more pronounced progression in girls. The survival probability at 1 year was 94% for male patients and 82% for female patients (p < 0.05) in this study. Urinary tract infections occurred more frequently in girls (p < 0.025) and were observed earlier. In addition, more girls had impaired renal function, developed end-stage renal disease and showed growth retardation; these differences, however, were not significant. For the children in this study, however, our results indicate that the long-term prognosis in the majority of cases is better throughout childhood and youth than often stated.

Adolescent↗
PubMed1996

Current status of DNA diagnosis for hereditary nephropathies.

The molecular genetic defect of many hereditary nephropathies has been assigned to a specific chromosomal region or has even been identified. While the localization of a gene permits an indirect genotype analysis to estimate the risk status of a close relative of a patient with a proven clinical diagnosis, it is not possible to confirm a diagnosis in case of inconclusive clinical data. In some nephropathies, the gene has been cloned and mutations identified. By demonstrating the molecular genetic defect in these patients, the diagnosis can be ensured and an easily assessible method of carrier detection can be offered. The possibilities and limitations of DNA diagnosis in some important nephropathies are outlined.

DNA↗
PubMed1996

Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease.

Spinal muscular atrophy (SMA) is a frequent autosomal recessive neurodegenerative disorder leading to weakness and atrophy of voluntary muscles. The survival motor-neuron gene (SMN), a strong candidate for SMA, is present in two highly homologous copies (telSMN and cenSMN) within the SMA region. Only five nucleotide differences within the region between intron 6 and exon 8 distinguish these homologues. Independent of the severity of the disease, 90%-98% of all SMA patients carry homozygous deletions in telSMN, affecting either exon 7 or both exons 7 and 8. We present the molecular analysis of 42 SMA patients who carry homozygous deletions of telSMN exon 7 but not of exon 8. The question arises whether in these cases the telSMN is truncated upstream of exon 8 or whether hybrid SMN genes exist that are composed of centromeric and telomeric sequences. By a simple PCR-based assay we demonstrate that in each case the remaining telSMN exon 8 is part of a hybrid SMN gene. Sequencing of cloned hybrid SMN genes from seven patients, as well as direct sequencing and single-strand conformation analysis of all patients, revealed the same composition in all but two patients: the base-pair differences in introns 6 and 7 and exon 7 are of centromeric origin whereas exon 8 is of telomeric origin. Nonetheless, haplotype analysis with polymorphic multicopy markers, Ag1-CA and C212, localized at the 5' end of the SMN genes suggests different mechanisms of occurrence, unequal rearrangements, and gene conversion involving both copies of the SMN genes. In approximately half of all patients, we identified a consensus haplotype, suggesting a common origin. Interestingly, we identified a putative recombination hot spot represented by recombination-stimulating elements (TGGGG and TGAGGT) in exon 8 that is homologous to the human deletion-hot spot consensus sequence in the immunoglobulin switch region, the alpha-globin cluster, and the polymerase alpha arrest sites. This may explain why independent hybrid SMN genes show identical sequences.

Biomarkers↗
PubMed1996

Further arguments for non-fortuitous association of Potter sequence with XYY males.

Although large studies on sex chromosome abnormalities have not detected a higher incidence of malformations in 47,XYY males, several case reports suggest that there is an association between renal agenesis or cystic dysplasia of the kidney and XYY status. The authors report 3 further infants with XYY karyotype who had urogenital malformations leading to Potter sequence. On the basis of our observations and review of the literature, we suggest that the XYY syndrome and Potter sequence are more significantly associated than expected by pure coincidence.

Abnormalities, Multiple↗
PubMed1995

Fine mapping of MEP1A, the gene encoding the alpha subunit of the metalloendopeptidase meprin, to human chromosome 6P21.

Meprins are kidney and intestinal proteases encoded by two distinct genes, MEP1A and MEP1B. MEP1A was previously mapped to human chromosome 6p, by the use of radiation and somatic cell hybrids, in the region containing the gene for autosomal recessive polycystic kidney disease (ARPKD). We now report the fine mapping of MEP1A using yeast artificial chromosome clones, and linkage analysis of ARPKD families. The results from both physical and genetic mapping exclude MEP1A as a candidate for ARPKD. These studies place MEP1A in a region more telomeric to 6p12 and closer to the HLA loci than previously reported. More specifically, MEP1A is localized between loci D6S272 and D6S282, close to D6S452, on human chromosome 6p21.2-p21.1. The more precise location of MEP1A will facilitate genetic studies of this locus and clarify the relation of this gene to others.

Alleles↗
PubMed1995

Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications.

OBJECTIVES: To describe the natural history in all types of proximal spinal muscular atrophy (SMA) and to propose a modified classification scheme that takes the long-term course of SMA into account. DESIGN: Patients with proximal SMA were studied prospectively and retrospectively in a genetic study that was based on clinical and family data. PATIENTS: Four hundred forty-five patients with SMA were ascertained since 1985 through various departments of neurology and neuropediatrics, institutes of human genetics, and the German muscular dystrophy association (Deutsche Gesellschaft für Muskelkranke, Freiburg, Germany). RESULTS: The study group was subdivided into patients with four types of SMA (ie, SMA types I, II, III, and IV) on the basis of achieved motor development and age at onset. Survival probabilities at 2, 4, 10, and 20 years of age were 32%, 18%, 8%, and 0%, respectively, in patients with SMA type I (those who were never able to sit) and 100%, 100%, 98%, and 77%, respectively, in patients with SMA type II (those who were able to sit but were unable to walk). Nineteen of 104 patients with SMA type II lost the ability to sit; this inability to sit was not of prognostic relevance. Patients with SMA type III (those who were able to walk [age at onset, younger than 30 years]) were subdivided into those with an age at onset before (SMA type IIIa) and after (SMA type IIIb) 3 years. The probabilities of being ambulatory at 10, 20, and 40 years after onset were 73%, 44%, and 34%, respectively, in patients with SMA type IIIa, and they were 97%, 89%, and 67%, respectively, in patients with SMA type IIIb. CONCLUSIONS: The definition of long-term characteristics of SMA is helpful in providing medical care to families with members who have SMA and also in providing important information for future genotype-phenotype studies and therapeutic trials of patients with SMA. Our data indicate that the widely used classification schemes did not consider the broad spectrum of SMA so a practical modification was suggested.

Child↗