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Biomedical subjects

G A Nicholson

Publications and source records attributed to G A Nicholson.

At least 19 recordsLinked to original sources
PubMed1998

Different patterns of obstetric complications in myotonic dystrophy in relation to the disease status of the fetus.

The obstetric histories of 26 women with myotonic dystrophy (DM), who had a total of 67 gestations, were reviewed retrospectively comparing gestations with affected (DM-fetuses) and unaffected fetuses (UA-fetuses). Second, the influence of gestation on the disease course and the personal attitude towards family planning in DM was assessed. Miscarriages and terminations occurred in 11 pregnancies. Of the 56 infants carried to term, 29 had or most likely had inherited the gene for DM from their affected mothers at the time of investigation; 18 (61%) in this series were affected by the congenital form of DM. Perinatal loss rate was 11% and associated with congenital DM. The rate of obstetric complications was significantly increased in all women. However, preterm labor was a major problem in gestations with DM-fetuses (55 vs. 20%), as was polyhydramnios (21% vs. none). While forceps deliveries or vacuum extractions were required in 21% of deliveries with DM-fetuses and only 5% of UA-fetuses, the frequency of Cesarean sections was similar in both groups (24 and 25%). Obstetric problems were inversely correlated with age at onset of maternal DM, while no effect of age at delivery or birth order on gestational outcome was seen. DNA analysis confirmed the diagnosis in 19 patients by the presence of enlarged CTG repeats (EcoRI-expansions) on chromosome 19. Of the 17 patients whose CTG repeat length was known, 59% were classified as E2 (corresponding to 500-1000 repeats), 24% as E1 (<500 repeats), while larger expansions (E3; 1000-1500 repeats, or E4; >1500 repeats) were seen in three patients (17%). Obstetric complications or congenitally affected children occurred in all maternal phenotypes and CTG repeat classes. Eight (31%) patients experienced a worsening of symptoms that was temporary, weight related in three cases, and persistent in five. With the exception of three patients, most new mothers were able to care for their families. To conclude, pregnant women with DM need constant obstetric monitoring and should be advised to deliver in centres with perinatal facilities.

Adult↗
PubMed1998

Genomic structure and physical mapping of C17orf1: a gene associated with the proximal element of the CMT1A-REP binary repeat.

C17orf1, a gene expressed in skeletal muscle and heart, was initially isolated from a fetal brain cDNA library and localized centromeric to and partially within the proximal CMT1A-REP element. A second gene, COX10, spans the distal CMT1A-REP element, and a duplicated exon of this gene is present in the proximal CMT1A-REP element. C17orf1 includes this duplicated COX10 exon within its sequence; however, the DNA strand opposite to that of the COX10 gene is utilized. We have determined the genomic organization of C17orf1 and found it to be oriented in the direction opposite to COX10. Analysis of the genomic structure of C17orf1 has revealed that it contains at least six exons and spans a length of at least 17 kb. All but one of the splice sites conform to the GT/AG rule, and in this case the splice acceptor site within intron 1 is GA instead of the expected AG. Sequencing and mapping analyses have shown that the centromeric boundary of the proximal CMT1A-REP element lies within intron 5. A 7-bp insertion, identified from genomic sequencing of cosmid clones and verified in the original cDNA clone and RT-PCR products, has extended the previously reported open reading frame from 591 to 756 bp. C17orf1 therefore encodes a 252-amino-acid protein.

Alkyl and Aryl Transferases↗
PubMed1998

A YAC-based transcript map of human chromosome 9q22.1-q22.3 encompassing the loci for hereditary sensory neuropathy type I and multiple self-healing squamous epithelioma.

Hereditary sensory neuropathy type I (HSN-I) is an autosomal dominant peripheral neuropathy, involving sensory and motor neurons. The disease involves distal sensory loss, distal muscle wasting and weakness, and variable neural deafness. The HSN-I locus has been mapped to a 3- to 4-cM genetic interval on chromosome 9q22.1-q22.3. As part of a positional cloning effort to identify the HSN-I gene, we have generated a YAC based transcript map that spans approximately 8 Mb between D9S318 and D9S1786. This transcript map encompasses both the HSN-I critical interval and the locus for multiple self-healing squamous epithelioma (MSSE, previously named ESS1). Forty two ESTs and six characterized genes have been localized across 10 YAC clones, within a framework of 19 genetic linkage markers. Three other characterized genes were localized immediately adjacent to this interval. We have accurately mapped two recently identified genes: NINJ1 was anchored to D9S12II, and the localization of the NOR1 gene was significantly refined. We have also investigated NOR1 and several other characterized genes that localize to chromosome 9q22 for a pathogenic role in HSN-I. This map provides candidate genes for HSN-I and MSSE and is an important step toward completing a functional map of this gene-rich interval.

Carcinoma, Squamous Cell↗
PubMed1998

No association of presenilin-1 intronic polymorphism and Alzheimer's disease in Australia.

We screened 703 Australian subjects for an intronic polymorphism in the presenilin-1 (PS-1) gene. PS-1 intronic allele 1 homozygosity was not associated with individuals with early- or late-onset sporadic Alzheimer's disease (EOAD or LOAD). Carriers for the PS-1 intronic allele 1 were also not associated with significantly increased risk for AD regardless of gender. Our results for the Australian population are consistent with those of recent reports for other populations and do not support the conclusion that the PS-1 intronic polymorphism is associated with AD.

Adult↗
PubMed1998

Charcot-Marie-Tooth disease: histopathological features of the peripheral myelin protein (PMP22) duplication (CMT1A) and connexin32 mutations (CMTX1).

The two most common subtypes of Charcot-Marie-Tooth (CMT) disease are CMT1A and CMTX1. To determine whether these different genetic entities display different morphological phenotypes we compared sural nerve biopsies of CMT1A patients due to PMP22 duplication with biopsies of CMTX1 patients with proven Connexin32 mutations. In CMT1A nerve biopsies we found a severe reduction in myelinated fiber density, hypermyelination as well as demyelination, and a high percentage of onion bulb formations. CMTX1 nerve biopsies showed significant differences: a higher myelinated fiber density, thinner myelin sheaths, more cluster formations, and only few onion bulb formations. Teased fibers studies in CMT1A patients showed features of demyelination and/or remyelination in almost all fibers. In contrast, teased fibers of CMTX1 patients were uniformly thinly myelinated with 5-10% active axonal degeneration and 15% segmental demyelination. Median nerve motor conduction velocities were significantly faster in CMTX1 patients (31.6+/-5.5 m/s) than in CMT1A patients (18.2+/-6.9 m/s). The possible roles of PMP22 and Connexin32 in the pathogenesis of CMT are discussed.

Adolescent↗
PubMed1998

Evidence for an X-linked genetic component in familial typical migraine.

Migraine is a common complex disorder that shows strong familial aggregation. There is a general increased prevalence of migraine in females compared with males, with recent studies indicating that migraine affects 18% of females compared with 6% of males. This preponderance of females among migraine sufferers coupled with evidence of an increased risk of migraine in first degree relatives of male probands but not in relatives of female probands suggests the possibility of an X-linked dominant gene. We report here the localization of a typical migraine susceptibility locus to the X chromosome. Of three large multigenerational migraine pedigrees two families showed significant excess allele sharing to Xq markers (P = 0.031 and P = 0.012). Overall analysis of data from all three pedigrees gave significant evidence in support of linkage and heterogeneity (HLOD = 3.1). These findings provide conclusive evidence that familial typical migraine is a heterogeneous disorder. We suggest that the localization of a migraine susceptibility locus to the X chromosome could in part explain the increased risk of migraine in relatives of male probands and may be involved in the increased female prevalence of this disorder.

Alleles↗
PubMed1998

Sperm DNA analysis in a Friedreich ataxia premutation carrier suggests both meiotic and mitotic expansion in the FRDA gene.

Friedreich ataxia is usually caused by an expansion of a GAA trinucleotide repeat in intron 1 of the FRDA gene. Occasionally, a fully expanded allele has been found to arise from a premutation of 100 or less triplet repeats. We have examined the sperm DNA of a premutation carrier. This man's leucocyte DNA showed one normal allele and one allele of approximately 100 repeats. His sperm showed an expanded allele in a tight range centering on a size of approximately 320 trinucleotide repeats. His affected son has repeat sizes of 1040 and 540. These data suggest that expansion occurs in two stages, the first during meiosis followed by a second mitotic expansion. We also show that in all informative carrier father to affected child transmissions, with the notable exception of the premutation carrier, the expansion size decreases.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Charcot-Marie-Tooth disease and Noonan syndrome with giant proximal nerve hypertrophy.

We report a family with Noonan syndrome (NS), giant proximal nerve hypertrophy, and hereditary motor sensory neuropathy type 1A (HMSN1A). Five members of a family were found to have clinical features of NS. In all cases, NS was associated with giant hypertrophy of proximal nerves and two individuals also exhibited café-au-lait spots. In one case, an 8-to-10-cm diameter pelvic mass was shown to be a grossly hypertrophied nerve, with histologic features of demyelination and remyelination. In addition, four of five family members affected with NS were found to have HMSN1A clinically and by demonstration of constitutional HMSN1A duplication on DNA testing. Linkage analysis for NS ruled out the involvement of the neurofibromatosis type 1 gene and the known NS locus in chromosome 12, supporting the existence of an additional NS locus.

Adolescent↗
PubMed1998

Efficient neurophysiologic selection of X-linked Charcot-Marie-Tooth families: ten novel mutations.

OBJECTIVE: To devise a neurophysiologic strategy to select X-linked Charcot-Marie-Tooth neuropathy syndrome (CMTX) families for connexin 32 mutation screening. BACKGROUND: Once the common chromosome 17 DNA duplication (CMT1A syndrome) has been excluded, clinical features are not sufficiently distinctive to select which of three genes (PMP22, Po, or connexin 32) should be screened for mutations. DESIGN: The yield of connexin 32 mutations was compared in possible CMTX families with clinical and genetic features of CMTX and probable CMTX families, defined by additional characteristic neurophysiologic features of CMTX. Of 232 CMT families with median motor nerve conduction velocities below 50 m/second (s) in affected men, 50 were found to have no CMT1A duplication and a pattern of inheritance compatible with CMTX (no man-to-man inheritance of CMT). These families were divided into 23 probable CMTX families (defined as having electrophysiologic indicators of CMTX), 23 possible CMTX families (with no neurophysiologic features of CMTX), and five unlikely CMTX families (with normal brainstem evoked auditory potentials [BAEPs]). RESULTS: The yield of mutations in the whole group was 25 mutations in 51 families (50%). Most probable CMTX families (21 of 23; 91%) had connexin 32 coding region mutations. Included in this group were 14 families with obligate female carriers; 11 of these had intermediate conduction velocities (>42 m/s) and nine (81%) had connexin 32 mutations. Only 3 of 23 (13%) possible CMTX families had connexin 32 mutations. One of five families with normal BAEPs in affected men had a connexin 32 mutation, and one had a Po Ala112Val mutation. Seventeen different mutations were found among 24 families, including 10 previously undescribed mutations (Leu9Trp, Ile28Thr, Ile30Thr, Ile127Met, Leu131Pro, Tyr154 stop, Pro158Ala, one base deletion of codon 158 causing stop at codon 195, Val192Phe, and Leu239Ile). CONCLUSIONS: The yield of connexin 32 mutations can be increased from approximately 6% of all CMT type I families to 91% of nonduplicated nondominant families with characteristic electrophysiologic changes of CMTX.

Amino Acid Substitution↗
PubMed1998

Determination of gene dosage at the PMP22 and androgen receptor loci by quantitative PCR.

UNLABELLED: Although many genetic diseases are caused by the presence of point mutations in respective genes, an increasing number of diseases are known to be caused by gene copy number changes. We report the development of a rapid and reliable PCR-based method for quantitation of gene copy number with sufficient sensitivity to detect single copy changes without the use of radioactive or fluorescent labeling. The sensitivity of this technique has been demonstrated by the detection of the DNA duplication or deletion occurring in two inherited peripheral neuropathies, Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), that are caused by a reciprocal duplication or deletion event on chromosome 17p11.2-12. This method relies on the comparison of the amount of PCR product generated from a potentially duplicated or deleted target sequence with the amount of product generated from a disomic reference gene. The value of this ratio (target PCR product:reference PCR product) indicates whether the target sequence is duplicated, deleted, or unchanged. Using primers from within a duplicated or deleted region (PMP22 gene and EW401) and from within a reference region (NF1 gene), we tested 50 CMT1A, 30 HNPP, and 50 unaffected individuals for the presence of a DNA duplication or deletion. TARGET: reference ratios of 1.58, 1.02, and 0.56 were detected for the CMT1A, unaffected, and HNPP groups, respectively. Thus, differentiation of the three groups of individuals was on the basis of gene copy number. This technique was successfully used to detect the difference in the X chromosome copy number between males and females (target:reference ratios of 1.1 and 2.3, respectively). This approach to the detection of DNA duplications and deletions is sensitive, accurate, and has potential applications in the quantitation of changes in gene copy number associated with diseases characterized by such chromosomal alterations.

Charcot-Marie-Tooth Disease↗
PubMed1997

The Charcot-Marie-Tooth binary repeat contains a gene transcribed from the opposite strand of a partially duplicated region of the COX10 gene.

Misalignment between the two elements of the CMT1A-REP binary repeat on chromosome 17p11.2-p12 causes two inherited peripheral neuropathies, Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies. This binary repeat contains repetitive DNA elements that include LINES, SINES, medium reiteration frequency repeats, and a transposon-like element. The COX10 gene has been mapped 10 kb centromeric to the distal CMT1A-REP element, and a portion of this gene is present in both the proximal and the distal CMT1A-REP elements. We report the isolation and characterization of a novel cDNA (C170RF1), which maps centromeric to and partially within the proximal CMT1A-REP element. Part of C170RF1 is transcribed from the opposite strand of the COX10 partial gene duplication present in the proximal CMT1A-REP element. This finding shows that C170RF1 and COX10 are being transcribed from opposite strands of identical DNA sequences that are separated by 1.5 Mb in the genome. RT-PCR analysis showed the proximal transcript was expressed in skeletal muscle. Sequence analysis identified an open reading frame encoding a 199-amino-acid protein. Zoo blot analysis showed that the transcript is conserved in nonhuman primates. The presence of a binary repeat contributes to the instability of this region of chromosome 17, yet two CMT1A-REP elements are present in the chimpanzee and all human populations. The presence of expressed sequences in both elements of the CMT1A-REP binary repeat could explain the maintenance of this repeat in humans.

Adult↗
PubMed1997

Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype.

Eleven early-onset dementia families, all with affected individuals who have either presented clinical symptoms of early onset familial Alzheimer's disease (EOFAD) or have been confirmed to have EOFAD by autopsy, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of presenilin-1 (PS-1) and -2 (PS-2) genes. Missense mutations were detected by direct sequence analysis of PCR products amplified from genomic DNA templates of affected individuals. Three pedigrees were attributable to known mutations in the PS-1 gene: P264L, E280A and the splice acceptor site (G to T) mutation, which results in the deletion of residues 290-319 of PS-1 (PS-1 delta 290-319). In a fourth pedigree, a novel PS-1 mutation was identified in exon 7 (M233T), which is homologous to a pathogenic PS-2 mutation (M239V), and is characterized by a very early average age of onset (before the age of 35). In one early onset case, another novel PS-1 mutation was identified in exon 8 (R278T). Of the five remaining families and the other early onset case, none have missense mutations in the PS-1 or PS-2 genes, or in exon 16 and 17 of the APP gene. Moreover, two of the PS-1 mutations, PS-1 delta 290-319 and R278T, are associated with the co-presentation of familial spastic paraparesis (FSP) in some of the affected family members. Our data raise the possibility that the phenotypic spectrum associated with PS-1 mutations may extend beyond typical FAD to include FSP, a disease heretofore unsuspected to bear any relationship to FAD. In addition, our data suggest that other novel EOFAD loci, in addition to APP and the presenilin genes, are involved in the aetiology of up to 50% of EOFAD cases.

Adult↗
PubMed1997

Fine mapping of the hereditary sensory neuropathy type I locus on chromosome 9q22.1-->q22.3: exclusion of GAS1 and XPA.

The peripheral neuropathy, hereditary sensory neuropathy type I (HSN-I) is an autosomal dominant degenerative disorder of sensory and motor neurons. The disease leads to distal sensory loss, distal muscle wasting and weakness, and variable neural deafness. The HSN-I locus was recently mapped to a large genetic interval on chromosome 9q22 that includes the candidate genes GAS1 and XPA. XPA mutations have been shown to cause peripheral neuropathy, and GAS1 is related to the PMP22 gene, which is critical in the pathogenesis of two other peripheral neuropathies. By undertaking extensive genetic linkage analysis within the candidate region, we have refined the HSN-I locus to a critical interval of 3-4 cM. GAS1, XPA, and several other genes that map within the interval initially identified for the disease locus have been investigated and excluded from playing a pathogenic role in HSN-I.

Cell Cycle Proteins↗
PubMed1996

Use of cosH1 probe in hereditary neuropathy with liability to pressure palsies: a reliable genetic test for demonstration of identical size of 17p11.2 deletion in unrelated patients.

We describe pulsed-field gel electrophoresis (PFGE) analysis of 10 unrelated Italian families and seven isolated cases with hereditary neuropathy with liability to pressure palsies (HNPP). Our sample includes patients with different clinical features, varying from classical liability to pressure palsies to ingravescent polyneuropathy. The frequency and the uniformity in size of the 17p11.2 deletion was evaluated by using cosH1 probe from the Charcot-Marie-Tooth neuropathy type 1A (CMT1A)-REP region. The presence of the deletion was demonstrated in all our patients; furthermore, the deletion was of identical size, although our patients had different clinical features. Molecular analysis of the 17p11.2 region by PFGE method proved to be a reliable and non-invasive method of diagnosis in HNPP cases both familial and isolated.

DNA Probes↗
PubMed1996

Three novel mutations and two variants in the gene for Cu/Zn superoxide dismutase in familial amyotrophic lateral sclerosis.

Autosomal dominant inheritance is exhibited by about 10% of cases of amyotrophic lateral sclerosis (ALS), a paralytic disorder characterized by the death of motor neurons in the brain and spinal cord. A subgroup of these familial cases are linked to mutations in the gene which codes for Cu/Zn superoxide dismutase (SOD1). We report three additional mutations occurring in the SOD1 gene in ALS patients and two single base pair variant changes. The single base pair change in an ALS family causes a glycine 93 to valine substitution, which is the fifth distinct amino acid change reported for the glycine 93 residue. One missense mutation in exon 5 would substitute neutral valine for the negatively-charged aspartate 124 (aspartate 124 to valine). An individual with an apparently sporadic case of ALS carries a three base pair deletion in exon 5 of the SOD1 gene. These three mutations bring to 38 the total number of distinct SOD1 mutations associated with familial ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1996

The gene for hereditary sensory neuropathy type I (HSN-I) maps to chromosome 9q22.1-q22.3.

Hereditary sensory neuropathy type I (HSN-I, also known as hereditary sensory and autonomic neuropathy type I (HSAN-I), or hereditary sensory radicular neuropathy) is an autosomal dominant disorder that is the most common of a group of degenerative disorders of sensory neurons. HSN-I was initially recognized as a disease that produced mutilating ulceration leading to amputation of digits (Fig. 1). It was given names such as familial ulcers with mutilating lesions of the extremities and perforating ulcers with osseous atrophy. The disease involves a progressive degeneration of dorsal root ganglion and motor neurons, leading to distal sensory loss and later distal muscle wasting and weakness and variable neural deafness. Sensory deficits include loss of all modalities, particularly loss of sensation to pain and temperature. Skin injuries may lead to chronic skin ulcers, osteomyelitis, and extrusion of bone fragments, especially the metatarsals. Onset of symptoms is in the second or later decades. We undertook a genome screen using linkage analysis in four Australian HSN-I kindreds. We now show that the HSN1 gene maps to an 8-centiMorgan (cM) region flanked by D9S318 and D9S176 on chromosome 9q22.1-q22.3. Multipoint linkage analysis suggests a most likely location at D9S287, within a 4.9-cM confidence interval.

Alleles↗
PubMed1996

Apolipoprotein E genotyping in Alzheimer's disease in an Australian sample.

BACKGROUND: Several previous studies have reported an increased frequency of the E4 allele of the gene for Apolipoprotein (APOE4) in both familial and sporadic Alzheimer's disease (AD). We report the results of a study of this association in an Australian clinic-base sample. AIM: To investigate the relationship between APOE4 frequency and AD in an Australian clinic-based sample and compare the results with previous studies. METHODS: Subject DNA was PCR amplified, enzymatically digested with Hha1 and the resulting fragments electrophoretically separated. The genotypes were ascertained according to the resulting fragment sizes and the resulting allele frequencies analysed by calculating a z-statistic for comparison of two proportions. RESULTS: The frequency of the APOE4 allele was 53% in the AD group and 11% in the control group. This difference is statistically significant. There was no significant difference in E4 allele frequencies between AD subjects with a family history and those without. At least one E4 allele was found in 26/30 (87%) of AD patients and 10/50 (20%) of controls. The allele frequencies of the control subjects used in this study were found to be consistent with those of several previous studies. CONCLUSION: The frequency of the APOE4 allele was significantly higher in AD subjects than in unaffected controls. This provides further evidence of an association between APOE4 and both familial and sporadic AD.

Alleles↗