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T Strachan

Publications and source records attributed to T Strachan.

At least 55 records · Page 3Linked to original sources
PubMed1995

Presymptomatic DNA and MRI diagnosis of neurofibromatosis 2 with mild clinical course in an extended pedigree.

Neurofibromatosis 2 (NF2), a dominantly inherited disorder, typically manifests as bilateral vestibular schwannomas and predisposes to other nervous system tumors. In this study, we present a large pedigree with a benign course of NF2 (mild Gardner type) characterized by slowly growing vestibular schwannomas but few other manifestations. The family was thoroughly investigated with neurologic, ophthalmologic, and neuro-otologic methods including gadolinium-enhanced MRI of the head and spine and DNA linkage analysis. In the clinical analysis of 22 family members, MRI was superior to neuro-otologic methods in the detection of asymptomatic tumors. Based on the DNA linkage analyses we identified the NF2 mutation carriers with a high degree of certainty. These DNA markers (CRYB2, NEFH, D22S268, and D22S280) can also be used for presymptomatic diagnosis in other NF2 families. Early detection of NF2 gene mutation carriers has become possible using linkage analysis in familial NF2. MRI screening of carriers will reveal presymptomatic vestibular schwannomas (and other CNS tumors), making early intervention possible, but an efficient treatment strategy to prevent deafness has not yet been established.

Adult↗
PubMed1994

Identification of a novel family of human endogenous retroviruses and characterization of one family member, HERV-K(C4), located in the complement C4 gene cluster.

We have identified a novel family of about 10-50 human endogenous retrovirus elements (HERVs) and have characterized one family member (HERV-KC4). This retrovirus element is integrated within intron 9 of and complement C4A genes and also in some C4B genes, and is a principal contribution to interlocus and interallelic length heterogeneity of C4 genes. The HERV-K(C4) sequence has a typical retrovirus structure with elements of gag, pol and env domains, flanked by two long terminal repeats (LTRs) and is similar to type A, B and D retroviruses. Multiple termination codons preclude the existence of long open reading frames, suggesting that the HERV-K(C4) sequence is no longer functional. Zoo blot hybridization reveals that New World monkeys appear to lack sequences similar to HERV-K(C4), suggesting that integration has occurred after the divergence of Old and New World monkeys. Retrotransposition of prototype viruses is presumed to have led to the amplification and integration of the members of the family in different loci, which in humans, appear to be dispersed over several chromosomes. The absence of the HERV-K(C4) element in some C4B genes in both humans and orangutangs indicate that the retrovirus inserted into the C4A gene after the duplication of the cluster. Subsequent spread of the HERV-K(C4) sequence to C4B genes presumably occurred by interlocus sequence exchange mechanisms, such as unequal crossover and gene conversion-like mechanisms.

Animals↗
PubMed1994

Molecular basis of splotch and Waardenburg Pax-3 mutations.

Pax genes control certain aspects of development, as mutations result in (semi)dominant defects apparent during embryogenesis. Pax-3 has been associated with the mouse mutant splotch (Sp) and the human Waardenburg syndrome type 1 (WS1). We have examined the molecular basis of splotch and WS1 by studying the effect of mutations on DNA binding, using a defined target sequence. Pax-3 contains two different types of functional DNA-binding domains, a paired domain and a homeodomain. Mutational analysis of Pax-3 reveals different modes of DNA binding depending on the presence of these domains. A segment of Pax-3 located between the two DNA-binding domains, including a conserved octapeptide, participates in protein homodimerization. Pax-3 mutations found in splotch alleles and WS1 individuals change DNA binding and, in the case of a protein product of the Sp allele, dimerization. These findings were taken as a basis to define the molecular nature of the mutants.

Animals↗
PubMed1994

Molecular pathology of 21-hydroxylase deficiency.

Steroid 21-hydroxylase deficiency is a recessively inherited disorder of adrenal steroidogenesis. Different clinical variants map to a single gene CYP21B, which maps within the HLA complex and is located about 30 kb proximal to a very closely related 21-hydroxylase pseudogene, CYP21A. The two CYP21 genes are located on highly homologous tandemly repeated 30kb units, facilitating interlocus sequence exchanges. One type of exchange, unequal crossover, can result in CYP21B gene deletion or replacement of a large segment of the CYP21B gene by the analogous segment of the CYP21A gene. Gene conversion-like mechanisms can result in replacement of a very small segment of CYP21B by the analogous CYP21A sequence, thereby introducing a deleterious CYP21A-specific mutation. The vast majority of point mutation alleles seem to be accounted for by only a few of the mutations copied from CYP21A and can be assayed by ASO hybridization or allele-specific amplification assays of selectively amplified CYP21B gene sequences. Genotype-phenotype correlations are largely as expected: mutations resulting in no or severely curtailed gene expression are associated with severe clinical phenotypes; those resulting in significant residual enzyme activity are associated with milder clinical phenotypes.

Adrenal Hyperplasia, Congenital↗
PubMed1994

PAX genes.

PAX genes are developmental control genes that encode transcription factors containing a DNA-binding paired domain. Mutations in three of the nine mouse genes (Pax1, Pax3 and Pax6) and two of the nine human genes (PAX3 and PAX6) are known to cause developmental defects. These defects are caused by loss-of-function alleles; pathogenesis occurs as a result of a half dosage of the PAX gene product in particular cells. Gain-of-function mutations have been implicated in cancer.

Animals↗
PubMed1994

A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p.

The limb-girdle muscular dystrophies are a clinically and genetically heterogeneous group of disorders. We have studied two large inbred families of different ethnic origin and excluded linkage to LGMD2 on chromosome 15q and SCARMD on chromosome 13. Proceeding to a genomic linkage search, we have now identified linkage to markers D2S134 and D2S136 on chromosome 2p (maximum lod score 3.57 at zero recombination). The phenotype in the two families was similar, with onset in the pelvic girdle musculature in the late teens and usually relatively slow progression. This work identifies a second locus for autosomal recessive limb-girdle muscular dystrophy.

Adolescent↗
PubMed1994

Germline mutations in the neurofibromatosis type 2 tumour suppressor gene.

The recent identification of the NF2 tumour suppressor gene has enabled large scale screening for pathological mutations in the gene. We have sought germline mutations in the NF2 gene by SSCP and heteroduplex analysis of cDNA and genomic DNA samples followed by cloning and sequencing of mutant alleles. In the present report we describe 11 putative pathological mutations, including five nonsense mutations, three short insertions or deletions causing frameshifts and three missense mutations. Most stop mutations and frameshift mutations were found in individuals expressing a severe phenotype while one of the three missense mutations was associated with a mild phenotype. Four unrelated NF2 patients of the 93 tested were found to have identical nonsense mutations caused by a C to T transition (C169) in a CpG dinucleotide, which is a potential mutational hotspot in the NF2 tumour suppressor gene.

Base Sequence↗
PubMed1994

PAX3 gene structure and mutations: close analogies between Waardenburg syndrome and the Splotch mouse.

The human PAX3 gene contains a paired box and a paired-type homeobox, and is believed to play a role in pattern formation in the embryo. We describe the exon-intron structure of the homeobox-containing part of PAX3, complementing earlier descriptions of the 5' part of the gene. Mutations in PAX3 have been described in patients with Type 1 Waardenburg syndrome, who have hearing loss and pigmentary abnormalities, while Splotch mice have mutations in the homologous mouse Pax-3 gene. We describe a series of patients who have previously unidentified PAX3 mutations. These include a chromosomal deletion, a splice-site mutation and an amino acid substitution which closely correspond to the molecular changes seen in the Splotch-retarded, Splotch and Splotch-delayed mouse mutants respectively. These mutations confirm that Waardenburg syndrome is produced by gene dosage effects and show that the phenotypic differences between Splotch mice and humans with Waardenburg syndrome are caused by differences in genetic background rather than different primary effects of the mutations.

Animals↗
PubMed1994

A gene for pachyonychia congenita is closely linked to the keratin gene cluster on 17q12-q21.

Pachyonychia congenita (PC) is a group of hereditary syndromes which have in common a hypertrophic dystrophy of the distal nail, and are associated with a variety of additional features, notably various dyskeratoses of skin and mucous membranes. The pathology is unknown but the array of clinical features suggests the possibility of a keratin abnormality. In the present report we describe linkage analyses in a large PC pedigree of the Jackson-Lawler type, a subtype which is characterised by multiple epidermal cysts, hair abnormalities, and natal teeth. The disease locus in this family was found to be tightly linked to markers mapping within, or very close to, the keratin type I cluster at 17q12-q21; maximum lod scores for linkage of the disease to a KRT10 polymorphism and to D17S800, a marker known to be very tightly linked to KRT10, were respectively +4.51 and +7.73, both at theta = 0.00. Although always likely, our findings provide strong evidence of a keratin gene anomaly underlying an inherited disorder affecting epidermis, nail, hair, and mucosa. These findings permit testing to see if pachyonychia congenita shows any locus heterogeneity and suggest specific candidate keratin genes for mutation searching studies. In addition, they suggest a role for keratins in the phenomenon of natal dentition.

Chromosomes, Human, Pair 17↗
PubMed1994

Diffuse bilateral cerebral astrocytomas with atypical neuroimaging studies.

The authors describe the clinical behavior of eight patients with cerebral astrocytomas, in whom computerized tomography (CT) or magnetic resonance (MR) imaging of the brain was characterized by diffuse bilateral cerebral hemisphere tissue density abnormalities and minimal focal mass effect. Five patients were newly diagnosed, and three others had been treated for focal low-grade astrocytoma. Histological diagnoses included anaplastic astrocytoma (three patients), low-grade astrocytoma (three patients), glioblastoma (one patient), and gliosis with later development of glioblastoma (one patient). In five patients, brain tumor was not suspected from the neuroimaging studies, the findings of which were mistaken for radiation leukoencephalopathy, vasogenic edema, or multiple sclerosis. Serial CT scans or MR images undertaken over intervals of 3 to 184 weeks showed progression of abnormal tissue densities in seven patients and multifocal contrast-enhancing masses developed on CT scan in two patients. An autopsy in each of four patients showed diffuse cerebral infiltration by astrocytoma. It is concluded that neuroimaging studies in some patients with diffusely infiltrating cerebral astrocytoma are atypical for neoplasm and can be mistaken for other diseases, especially those that predominantly affect cerebral hemisphere white matter.

Adolescent↗
PubMed1994

Transcription of HLA-G transgenes commences shortly after implantation during embryonic development in mice.

We studied the pattern of transcription of a human HLA-G transgene in mice using polymerase chain reaction (PCR) techniques. Transcription of the HLA-G transgene commenced in cells derived from embryos as soon as 48 hr after implantation of embryos in the uterine wall and continued for at least a further 48 hr during embryonic development. HLA-G transcripts were also present in RNA extracted from thymus, spleen and liver of adult HLA-G transgenic mice, although transcripts were not detected in RNA from any other tissues except testes of male transgenic mice. These results demonstrate that the restricted pattern of HLA-G transcription in embryo-derived trophoblast cells during the first trimester of human pregnancy is reproducible in mice. This suggests that transcription factors required for a highly regulated pattern of gene expression during embryonic development are present in murine trophoblast cells and provide a means to investigate the factors and study the consequences of HLA-G expression during development of the embryo.

Animals↗
PubMed1994

A mutation in the neurofibromatosis type 2 tumor-suppressor gene, giving rise to widely different clinical phenotypes in two unrelated individuals.

We have sought mutations in the recently identified neurofibromatosis type 2 (NF2) tumor-suppressor gene in a large panel of NF2 patients, using PCR-based SSCP and heteroduplex analysis, followed by cloning and sequencing of appropriate PCR products. Two unrelated NF2 patients were found to have identical nonsense mutations caused by a C-to-T transition in a CpG dinucleotide that is a potential mutational hot spot in the NF2 tumor-suppressor gene. Unexpectedly, the two individuals had widely different clinical phenotypes, representing the severe Wishart and mild Gardner clinical subtypes. Analysis of DNA samples from different tissues of the mildly affected patient suggests that he is a somatic mosaic for the mutation.

Adolescent↗
PubMed1993

A clinical, genetic and audiological study of patients and families with bilateral acoustic neurofibromatosis.

The neurofibromatoses consist of at least two distinct autosomal dominant hereditary disorders. Neurofibromatosis type 1 (NF1) is due to a lesion on chromosome 17q. Neurofibromatosis type 2 (NF2) is caused by a defect on chromosome 22q. The hallmark of NF2 is the development, in the second and third decades, of bilateral acoustic neuromas. NF1 is characterized by the appearance of café-au-lait spots and neurofibromas in addition to iris hamartomas, or Lisch nodules, of the eye, during the first and second decades. Ten families were personally studied. A total of 16 members were found to be affected with NF2. A protocol for evaluation and review of subjects and relatives of NF2 families is proposed. A team approach, coordinating the expertise of multiple specialties is recommended.

Adolescent↗
PubMed1993

Mutations in the PAX3 gene causing Waardenburg syndrome type 1 and type 2.

Waardenburg syndrome (WS) is a combination of deafness and pigmentary disturbances, normally inherited as an autosomal dominant trait. The pathology involves neural crest derivatives, but WS is heterogeneous clinically and genetically. Some type I WS families show linkage with markers on distal 2q and in three cases the disease has been attributed to mutations in the PAX3 gene. PAX3 encodes a paired domain, a highly conserved octapeptide and probably also a paired-type homeodomain. Here we describe a further three PAX3 mutations which cause WS; one alters the octapeptide motif plus the presumed homeodomain; a second alters all three elements and the third alters the paired box alone. The latter occurs in a family with probable type 2 WS, a clinical variant usually considered not to be allelic with type 1 WS.

Amino Acid Sequence↗
PubMed1993

A de novo pathological point mutation at the 21-hydroxylase locus: implications for gene conversion in the human genome.

More than two hundred characterized 21-hydroxylase deficiency alleles appear to result exclusively from sequence exchanges involving the 21-hydroxylase gene (CYP21B) and a closely related pseudogene (CYP21A). Gene conversion-like events have also been reported in many other human gene clusters, but in the absence of a de novo mutation, the alternative explanation of a multiple recombination is possible. We now report a de novo pathological mutation at the 21-hydroxylase locus. DNA sequence analysis suggests that the mutation arose by a microconversion event involving exchange of up to 390 nucleotides between maternal CYP21A and CYP21B genes. This putative de novo gene conversion event appears to be the first characterized in humans.

Adrenal Hyperplasia, Congenital↗
PubMed1993

A disease-associated germline deletion maps the type 2 neurofibromatosis (NF2) gene between the Ewing sarcoma region and the leukaemia inhibitory factor locus.

RFLP typing of members of a neurofibromatosis type 2 (NF2) family suggested that affected individuals were hemizygous at the neurofilament heavy chain (NEFH) locus, possibly as a result of a disease-associated deletion. Conventional karyotyping revealed no evidence for a deletion and all or a majority of the affected family members were heterozygous for closely linked markers which mapped proximal to the NEFH locus (D22S1 and D22S56) and for the distal marker D22S32. FISH analysis confirmed a disease-associated germinal deletion on 22q which encompassed the NEFH locus, which is known to be very closely linked to NF2, but did not extend as far as the proximal Ewing sarcoma region or the distal leukaemia factor (LIF) locus. PFGE analysis with a LIF cosmid subclone identified patient-specific NotI and MluI fragments and suggested that the deletion is about 700 kb in length. Although this large deletion could be expected to eliminate a considerable fraction, and possibly all of the NF2 gene, the resulting phenotype is the mild, so-called Gardner subtype of NF2. The deletion should provide a useful mapping resource for characterising the chromosomal region containing the NF2 locus.

Alleles↗