Two novel mutations (L32P) and (G85N) among five different missense mutations in six Danish families with Fabry's disease.
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Base Sequence↗
Biomedical subjects
N Dahl
Publications and source records attributed to N Dahl.
Autosomal dominant cerebellar ataxia deafness and narcolepsy.
A new autosomal dominant syndrome in a Swedish pedigree is described. Five patients were affected with cerebellar ataxia and sensorineural deafness. Four of these patients had symptoms of narcolepsy. Optic atrophy, other neurological abnormalities and psychiatric symptoms developed with increasing disease duration. Three patients had non-neurological disease in addition, including diabetes mellitus in two and hypertrophic cardiomyopathy in one. Autopsy with neuropathological examination was performed in one case. Molecular studies focused on the short arm of chromosome 6, including the HLA DR2 locus associated with narcolepsy and the (CAG)n repeat at the spinocerebellar ataxia type 1 (SCA1) locus. Biochemical investigation of muscle biopsy of one case indicated mitochondrial dysfunction with selective decrease in ATP production for substrates that normally give the highest rates. The activity of glutamate dehydrogenase was reduced, indicating a low mitochondrial density. We postulate an autosomal dominant genetic factor responsible for this syndrome. Linkage was excluded to HLA DR2, and a normal sized SCA1 repeat was observed. We conclude that a locus predisposing to ataxia, deafness and narcolepsy exists outside this region of chromosome 6.
Adolescent↗
Inversion of the IDS gene resulting from recombination with IDS-related sequences is a common cause of the Hunter syndrome.
We have recently described the identification of a second IDS locus (IDS-2) located within 90 kb telomeric of the IDS gene (Bondeson et al. submitted). Here, we show that this region is involved in a recombination event with the IDS gene in about 13% of patients with the Hunter syndrome. Analysis of the resulting rearrangement at the molecular level showed that these patients have suffered a recombination event that results in a disruption of the IDS gene in intron 7 with an inversion of the intervening DNA. Interestingly, all of the six cases with a similar type of rearrangement showed recombination between intron 7 of the IDS gene and sequences close to exon 3 at the IDS-2 locus implying that these regions are hot spots for recombination. Analysis by nucleotide sequencing showed that the inversion is caused by recombination between homologous sequences present in the IDS gene and the IDS-2 locus. No detectable deletions or insertions were observed as a result of the recombination event. The results in this study have practical implications for diagnosis of the Hunter syndrome.
Base Sequence↗
Noonan syndrome with café-au-lait spots and multiple lentigines syndrome are not linked to the neurofibromatosis type 1 locus.
Noonan syndrome, multiple lentigines syndrome (LEOPARD syndrome), Watson syndrome and neurofibromatosis type 1 share certain clinical manifestations. We present a linkage analysis using microsatellite markers located in the neurofibromatosis type 1 region at 17q11 in a family with Noonan syndrome and café-au-lait spots and in another family with multiple lentigines syndrome. No linkage of the disease to the neurofibromatosis type 1 locus was found in the families investigated. On the basis of our results, we suggest that neither familial multiple lentigines syndrome nor Noonan syndrome is caused by a defect in the neurofibromatosis type 1 gene.
Cafe-au-Lait Spots↗
Presence of an IDS-related locus (IDS2) in Xq28 complicates the mutational analysis of Hunter syndrome.
A deficiency of the enzyme iduronate-2-sulfatase (IDS) is the cause of Hunter syndrome (mucopolysaccharidosis type II). Here, we report a study of the human IDS locus at Xq28. An unexpected finding was an IDS-related region (IDS2) which is located on the telomeric side of the IDS gene within 80 kb. We have identified sequences in this locus that are homologous to exons 2 and 3 as well as sequences homologous to introns 2, 3 and 7 of the IDS gene. The exon 3 sequences in the IDS gene and in the IDS2 locus showed 100% identity. The overall identities of the other identified regions were 96%. A locus for DXS466 was also found to be located close to IDS2. The existence of the IDS2 locus complicates the diagnosis of mutations in genomic DNA from patients with Hunter syndrome. However, information about the IDS2 locus makes it possible to analyze the IDS gene and the IDS2 locus separately after PCR amplification.
Base Sequence↗
New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease.
Analysis of the connexin32 gene in patients with X-linked Charcot-Marie-Tooth disease shows mutations distributed throughout the molecule, with all domains affected except the fourth transmembrane domain and the distal carboxy terminus. Sequence analysis of DNA from 19 unrelated patients detected six novel mutations and three previously reported mutations. Identification of additional mutations extends the distribution of connexin32 mutations in X-linked Charcot-Marie-Tooth disease and shows that specific mutations recur in additional families.
Amino Acid Sequence↗
Deletion mapping of X-linked mixed deafness (DFN3) identifies a 265-525-kb region centromeric of DXS26.
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Base Sequence↗
Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X inactivation assigns the MTM1 gene to a 600-kb region.
A young girl with a clinically moderate form of myotubular myopathy was found to carry a cytogenetically detectable deletion in Xq27-q28. The deletion had occurred de novo on the paternal X chromosome. It encompasses the fragile X (FRAXA) and Hunter syndrome (IDS) loci, and the DXS304 and DXS455 markers, in Xq27.3 and proximal Xq28. Other loci from the proximal half of Xq28 (DXS49, DXS256, DXS258, DXS305, and DXS497) were found intact. As the X-linked myotubular myopathy locus (MTM1) was previously mapped to Xq28 by linkage analysis, the present observation suggested that MTM1 is included in the deletion. However, a significant clinical phenotype is unexpected in a female MTM1 carrier. Analysis of inactive X-specific methylation at the androgen receptor gene showed that the deleted X chromosome was active in approximately 80% of leukocytes. Such unbalanced inactivation may account for the moderate MTM1 phenotype and for the mental retardation that later developed in the patient. This observation is discussed in relation to the hypothesis that a locus modulating X inactivation may lie in the region. Comparison of this deletion with that carried by a male patient with a severe Hunter syndrome phenotype but no myotubular myopathy, in light of recent linkage data on recombinant MTM1 families, led to a considerable refinement of the position of the MTM1 locus, to a region of approximately 600 kb, between DXS304 and DXS497.
Adult↗
X-linked progressive mixed deafness: a new microdeletion that involves a more proximal region in Xq21.
We report a large two-generation pedigree with seven affected males segregating for an X-linked mixed conductive sensorineural deafness. The patients present with atypical Mondini-like dysplasia, dilated petrous facial canal, dilatation of the internal auditory meatus fully connected with enlarged cochlear canals, and, in one patient, a wide bulbous posterior labyrinth. Obligatory carrier females are mildly affected. Molecular characterization of this family revealed a deletion of locus DXS169, in Xq21.1. Loci DXS72 and DXS26, which, respectively, flank DXS169 proximally and distally, were intact. Since a gene responsible for X-linked progressive mixed deafness with perilymphatic gusher (DFN3) has previously been assigned by deletion mapping to a slightly more distal interval between DXS26 and DXS121, this study indicates either two different deafness genes or the involvement of a very large region in Xq21.
Ear, Inner↗
Age-dependent differences in insulin secretion and intracellular handling of insulin in isolated pancreatic islets of the rat.
Insulin secretory response to glucose changes with age. To elucidate age-dependent differences in pancreatic islet responsiveness to glucose, isolated islets from rats one week, three months and 14 months old were investigated in vitro. At three months of age, islet insulin secretion was increased five-fold by an acute glucose challenge. There was a significantly lower insulin response in both younger and older age groups. Islet insulin biosynthesis, as determined by the rate of incorporation of radioactive leucine into immunoprecipitable insulin, was lower at three months of age than at one week or 14 months. Insulin content was lowest in islets from the youngest rats and increased with age. The capacity for islet intracellular degradation of insulin was estimated according to the disappearance of tritiated leucine-labelled insulin during a 24-hour chase incubation. At a high glucose concentration, virtually no insulin was degraded intracellularly in islets from three-month-old rats, whereas islets from both younger and older animals showed a significant degradative capacity. High activities of a number of lysosomal enzymes in islets from one-week-old rats could account for the high degradative capacity and relatively low insulin content of these islets. Thus, low insulin response to glucose during early development may depend primarily on low insulin stores. However, during ageing, when islets are characterised by high insulin content, low response may depend primarily on impairment of beta-cell stimulus-secretion coupling, with high intracellular degradation of insulin resulting secondarily from an accumulation of insulin in the islets.
Aging↗
Complex genetic counseling and exclusion of Duchenne muscular dystrophy in a twin pregnancy after in vitro fertilization (IVF).
A twin pregnancy following in vitro fertilization-embryo transfer coincidentally at risk for the X-linked recessive Duchenne muscular dystrophy is described. First-trimester prenatal diagnosis by transabdominal chorionic villus samplings on the dichorionic placentae and molecular linkage analysis could exclude the disorder in both fetuses. Genetic counseling and prenatal diagnosis were particularly complex due to the twin pregnancy, the need for linkage analysis, and confined placental mosaicism 45,X/46XX in one of the fetuses. All parties should be aware that additional invasive diagnostic procedures in the second trimester might be required. It is proposed that, in similar situations, only one, arguably two, fertilized egg be transferred at a time to facilitate prenatal diagnosis and decision making for these rare couples. This problem, however, may be increasingly overcome by preimplantation diagnosis.
Adult↗
The gene for the familial form of incontinentia pigmenti (IP2) maps to the distal part of Xq28.
Linkage data for familial incontinentia pigmenti (IP2) and 17 X chromosomal markers are reported. The linkage previously found between IP2 and the F8C locus is confirmed (Z max = 11.85 at theta = 0.028). Linkage is established with distal markers DXS1108 (Z max = 10.06 at theta = 0.00) and DXYS154 (Z = 9.07 at theta = 0.019). Multipoint analysis supports the distal localization of the IP2 gene with respect to the F8C locus.
Animals↗
Dinucleotide repeat polymorphism at the DXS1684 locus.
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Base Sequence↗
X linked myotubular myopathy (MTM1) maps between DXS304 and DXS305, closely linked to the DXS455 VNTR and a new, highly informative microsatellite marker (DXS1684).
The locus for X linked recessive myotubular myopathy (MTM1) has previously been mapped to Xq28 by linkage analysis. We report two new families that show recombination between MTM1 and either DXS304 or DXS52. These families and a third previously described recombinant family were analysed with two highly polymorphic markers in the DXS304-DXS52 interval, the DXS455 VNTR and a newly characterised microsatellite, DXS1684 (82% heterozygosity). These markers did not recombine with MTM1 in the three families. Together with the recent mapping of an interstitial X chromosome deletion in a female patient with moderate signs of myotubular myopathy, our data suggest the following order of loci in Xq28: cen-DXS304-(DXS455, MTM1)-DXS1684-DXS305-DXS52-tel. This considerably refined localisation of the MTM1 locus should facilitate positional cloning of the gene. The availability of highly polymorphic and very closely linked markers will markedly improve carrier and prenatal diagnosis of MTM1.
Base Sequence↗
Strong founder effect for the fragile X syndrome in Sweden.
We analyzed the FRAXAC2 and DXS548 microsatellites in normal and fragile X chromosomes from Sweden and the Czech Republic in order to investigate a possible founder effect for chromosomes carrying a fragile X mutation. We report a much stronger linkage disequilibrium between the marker haplotypes and the disease in Swedish fragile X chromosomes than in Czech and most other previously studied Caucasian populations. Two haplotypes accounted for 64% of Swedish fragile X chromosomes and for only 14% of normal chromosomes. Neither of these two haplotypes was found in Czech chromosomes, but the most common Swedish fragile X haplotype is the same as that reported to be predominant in Finnish fragile X patients. Linkage disequilibrium was observed in the Czech fragile X chromosomes but the haplotypes were more diverse and similar to those observed in other Caucasian populations. The most prevalent Swedish fragile X haplotype was traced back from affected males to common ancestors in the early 18th century. This indicates an apparently silent segregation of fragile X alleles through up to nine generations. The geographical distribution of the two major at-risk haplotypes in Sweden suggests that they were present among early settlers in different parts of the country.
Chi-Square Distribution↗
A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12.3: the first 2,253 cases.
We report the results of a 14-center collaborative study of genotype-phenotype correlations in 318 fragile X families; these families comprised 2,253 individuals, 1,344 of whom carried a fragile X mutation and 693 of whom had a typical full fragile X mutation. This study demonstrates that direct DNA diagnosis establishes the genotype at the FRAXA-FMR-1 locus. There was a significantly higher prevalence of "mosaic" cases among males who carry a full mutation (12%) than among females who carry a full mutation (6%); the mosaic males had a larger expansion than did the mosaic females. Mental status of premutated individuals did not differ from that of those with a normal genotype. Both the abnormal methylation of the FMR-1-EagI site and the size of the expansion were highly correlated with cytogenetics, facial dysmorphism, macroorchidism, and mental retardation (MR). Among female carriers of a full mutation, those with MR had significantly larger expansion than did those without MR. Among 164 independent couples, 3 unrelated husbands carried a premutation that suggests that the prevalence of fragile X premutations in the general population is approximately 0.9% of the X chromosomes. Our data validate the use of direct DNA testing for fragile X diagnosis as well as for carrier identification and support and complete the established relationships among the DNA results and the cytogenetic, physical, and psychological aspects of the disease.
Adolescent↗
New X-linked syndrome with severe mental retardation, severely impaired vision, severe hearing defect, epileptic seizures, spasticity, restricted joint mobility, and early death.
A family with an X-linked mental retardation syndrome involving seven children in two generations is reported. The syndrome includes microcephaly, severe mental retardation, optic atrophy with severely impaired vision or blindness, a severe hearing defect, spasticity, epileptic seizures, restricted movement of the large joints, and death in infancy or early childhood. We conclude that this is a distinct, previously unrecognized X-linked mental retardation syndrome.
Abnormalities, Multiple↗
Gaucher disease (Norrbottnian type III): probable founders identified by genealogical and molecular studies.
Gaucher disease type III (GD) is found at a high frequency in northern Sweden. The contemporary Swedish index families are found in two geographically distinct clusters with the highest world-wide frequency of type III GD. A single T-to-C transition in exon 10 has previously been identified in patients from one of the two isolates and we report there the same mutation in the second isolate. Mutational analysis was combined with a genealogical reconstruction of 19 contemporary index families. Both clusters were traced back to two corresponding pairs of ancestors over a 9-13 generation span. Molecular studies show that the two clusters are compatible with a single founder who arrived in northern Sweden in or before the 16th century.
DNA Mutational Analysis↗