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Biomedical subjects

S Malcolm

Publications and source records attributed to S Malcolm.

At least 19 recordsLinked to original sources
PubMed1999

Proteolipid protein gene: Pelizaeus-Merzbacher disease in humans and neurodegeneration in mice.

The dosage of the myelin gene and mutant forms of the protein can affect the CNS and PNS. Pelizaeus-Merzbacher disease (PMD) is a myelin disorder of the CNS that arises from both mutational mechanisms. Investigating the molecular basis of PMD in patients and animal models is furthering our understanding of the disease, dosage sensitivity and proteolipid protein function during myelinogenesis.

Animals↗
PubMed1998

The toxicological effects following the ingestion of chinook salmon from the Great Lakes by Sprague-Dawley rats during a two-generation feeding-reproduction study.

A two-generation reproduction-feeding study was undertaken with Sprague-Dawley rats to ascertain the effects of ingesting chinook salmon fillets caught in the Credit River, which empties into Lake Ontario (LO), or in the Owen Sound region of Lake Huron (LH). Rats (30/sex/group) were randomly assigned to groups whose dietary protein consisted of casein and/or lyophilized salmon [Group 1: 20% casein (controls); Group 2: 15% casein + 5% LO salmon (LO-5%); Group 3: 20% LO salmon (LO-20%); Group 4: 15% casein + 5% LH salmon (LH-5%); Group 5: 20% LH salmon (LH-20%)]. After 70 days on test, the males and females were mated on a 1:1 basis within diet groups. Approximately 70 days postweaning, one F1 male and one F1 female from 24 litters were mated within diet groups, avoiding sibling matings. At weaning, the F0 and F1 adults and the F1 and F2 neonates not randomly selected for further testing were necropsied. Evaluated parameters included growth, feed consumption, organ weights, reproduction indices, serum chemistry, hematology, and coagulation times. The only statistically significant effects which were present in both generations were increased relative liver and kidney weights of both sexes in the LO-20% and LH-20% groups; the LH-20% females had lower alanine transaminase activity than the controls; the controls had lower creatinine levels than the fish groups and the LO-20% females; the LH-20% and LO-20% males had a lower blood urea nitrogen than the controls; and the LH-20% females had a heavier terminal body weight than the controls and a lower number of red blood cells, hematocrit, hemoglobin values, and mean platelet volume. There was a tendency for the fish-fed groups to grow faster, eat more feed, and have larger litters with heavier pups. Overall, there was little to suggest that the myriad of contaminants in chinook salmon from the Great Lakes presented an appreciable toxicological risk to Sprague-Dawley growth and reproduction.

Animal Feed↗
PubMed1998

Fibroblast growth factor receptors: lessons from the genes.

The fibroblast growth factor receptors (FGFRs) are a family of transmembrane tyrosine kinases involved in signalling via interactions with the family of fibroblast growth factors (FGFs). Genetic findings have provided a way of dissecting these interactions. Mutations in three members of the FGFR family have been found in patients with birth defects involving craniosynostosis (premature fusion of the cranial sutures) or skeletal abnormalities. Analyses of the spectrum of mutations found predict that many of them will result in ligand-independent activation of the receptors. Amino acids have also been identified that are likely to be important in determining the specificity of FGFR-FGF interactions.

Amino Acid Sequence↗
PubMed1998

Pelizaeus-Merzbacher disease: identification of Xq22 proteolipid-protein duplications and characterization of breakpoints by interphase FISH.

Pelizaeus-Merzbacher disease (PMD) is an X-linked, dysmyelinating disorder of the CNS. Duplications of the proteolipid protein (PLP) gene have been found in a proportion of patients, suggesting that, in addition to coding-region or splice-site mutations, overdosage of the gene can cause PMD. We show that the duplication can be detected by interphase FISH, using a PLP probe in five patients and their four asymptomatic carrier mothers. The extent of the duplication was analyzed in each family by interphase FISH, with probes from a 1. 7-Mb region surrounding the PLP gene between markers DXS83 and DXS94. A large duplication >=500 kb was detected, with breakpoints that differed, between families, at the proximal end. Distinct separation of the duplicated PLP signals could be seen only on metaphase chromosomes in one family, providing further evidence that different duplication events are involved. Quantitative fluorescent multiplex PCR was used to confirm the duplication in patients, by the detection of increased copy number of the PLP gene. Multiallelic markers from the duplicated region were analyzed, since the identification of two alleles in an affected boy would indicate a duplication. The majority of boys were homozygous for all four markers, compared with their mothers, who were heterozygous for one to three of the markers. These results suggest that intrachromosomal rearrangements may be a common mechanism by which duplications arise in PMD. One boy was heterozygous for the PLP marker, indicating a duplication and suggesting that interchromosomal rearrangements of maternal origin also can be involved. Since duplications are a major cause of PMD, we propose that interphase FISH is a reliable method for diagnosis and identification of female carriers.

Central Nervous System Diseases↗
PubMed1998

Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis.

The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are caused by the loss of function of imprinted genes in proximal 15q. In approximately 2%-4% of patients, this loss of function is due to an imprinting defect. In some cases, the imprinting defect is the result of a parental imprint-switch failure caused by a microdeletion of the imprinting center (IC). Here we describe the molecular analysis of 13 PWS patients and 17 AS patients who have an imprinting defect but no IC deletion. Heteroduplex and partial sequence analysis did not reveal any point mutations of the known IC elements, either. Interestingly, all of these patients represent sporadic cases, and some share the paternal (PWS) or the maternal (AS) 15q11-q13 haplotype with an unaffected sib. In each of five PWS patients informative for the grandparental origin of the incorrectly imprinted chromosome region and four cases described elsewhere, the maternally imprinted paternal chromosome region was inherited from the paternal grandmother. This suggests that the grandmaternal imprint was not erased in the father's germ line. In seven informative AS patients reported here and in three previously reported patients, the paternally imprinted maternal chromosome region was inherited from either the maternal grandfather or the maternal grandmother. The latter finding is not compatible with an imprint-switch failure, but it suggests that a paternal imprint developed either in the maternal germ line or postzygotically. We conclude (1) that the incorrect imprint in non-IC-deletion cases is the result of a spontaneous prezygotic or postzygotic error, (2) that these cases have a low recurrence risk, and (3) that the paternal imprint may be the default imprint.

Angelman Syndrome↗
PubMed1997

A gene for FG syndrome maps in the Xq12-q21.31 region.

FG syndrome is an X-linked recessive condition in which mental retardation is associated with congenital hypotonia, macrocephaly, characteristic face, and constipation. This syndrome was mapped by Zhu et al. [Cytogenet Cell Genet 1991;58:2091A] to Xq21.31-q22 by linkage analysis with a max lod score of 1.2 for the DXYS1X, DXS178, DXS101, and DXS94 loci and crossovers at DXS16 (Xp22.31) and DXS287 (Xq22.3). However, this mapping was only provisional and needed to be refined. In this paper, we report the results of a new linkage analysis performed on 10 families including that studied by Zhu et al. [1991]. Two-point analysis demonstrated linkage with DXS441 (Zmax = 3.39 at theta = 0.12) at Xq13. In addition, separate analysis of the lod scores obtained for the Xq13 markers suggested linkage exclusion for three families. Genetic heterogeneity was confirmed by analysis of the linkage results with the HOMOG program (max logL = 4.07, theta = 0, alpha = 0.65). Localization of one FG gene between DXS135 and DXS1066 was suggested by analysis of crossovers found in those three families which were assumed to be linked to Xq13 with a probability of 0.95 or more. This region could be reduced to the DXS135-DXS72 interval after combining our data with those from deletions previously described in males in the Xq13-q21 region.

Abnormalities, Multiple↗
PubMed1997

Hereditary demyelinating neuropathy of infancy. A genetically complex syndrome.

Nine cases are described of a demyelinating peripheral neuropathy that had an onset in infancy. The clinical features conformed to those of type III hereditary motor and sensory neuropathy or Dejerine-Sottas disease. All showed a severe neurological deficit and had profoundly reduced nerve conduction velocities. Amongst these cases we identified four novel point mutations in the peripheral myelin protein 22 (PMP22) gene. These were Ser72Trp, Ser76lle and Leu80Pro. The Ser72Trp mutation was dominantly inherited by a mother and son, both severely affected. Two novel mutations in the gene for P0 myelin protein were also detected. These were Ile134Thr in exon 3, and a complex rearrangement in exon 4. The remaining three patients had presumed autosomal recessive inheritance. In these, no abnormality for the PMP22 and P0 genes was detected and a mutation at another locus or loci seems probable. On nerve biopsy the final two cases were shown to be examples of hereditary neuropathy with focally folded myelin sheaths. One showed both bulbar and diaphragmatic involvement. It is concluded that hereditary demyelinating neuropathy of infancy is genetically heterogeneous. Mutational screening for the PMP22 and P0 genes and nerve biopsy are therefore merited in patients with a childhood demyelinating neuropathy that is more severe than usual and in whom a chromosome 17 duplication is not present.

Adolescent↗
PubMed1997

The phenotypic manifestations of chromosome 17p11.2 duplication.

Clinical and electrophysiological investigations and nerve biopsies were carried out on 61 patients shown to have a chromosome 17p11.2 duplication (hereditary motor and sensory neuropathy-HMSN Ia). Of these, 50 showed a Charcot-Marie-Tooth (CMT) phenotype and eight could be classified as having the Roussy-Lévy syndrome. Of the patients with a CMT phenotype, three had associated pyramidal signs and of these one had 'complicated' HMSN and also signs of cerebellar and bulbar involvement. Diaphragmatic weakness was present in three severely affected cases, one of whom also had denervation of the anal sphincter associated with faecal incontinence. One unusual case presented in middle life with incapacitating muscle cramps associated with calf hypertrophy and only mild clinical signs of neuropathy. Prominent distal sensory loss was a consistent feature in one family, resulting in acrodystrophic changes in several members. Concurrent focal peripheral nerve lesions were seen with both the CMT and Roussy-Lévy phenotypes, in seven patients. Upper limb motor nerve conduction velocity was 19.9 m/s +/- 1.3 (SEM), range 5-34 m/s. This corresponds to values previously obtained for autosomal dominant HMSN I. This series consisted mainly of older patients with more advanced disease. In contrast to the findings in younger patients, in their nerve biopsies, myelin thickness tended to be relatively reduced for axon size, indicating remyelination and/or hypomyelination; there was also regression of the onion bulbs. It is concluded that the possession of two copies of the peripheral myelin protein 22 gene within the duplicated region on chromosome 17p gives rise to a range of phenotypes and not solely to a CMT syndrome, and that the pattern of histological change in the peripheral nerves alters with advance of the disease.

Adolescent↗
PubMed1997

IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome.

The Jervell and Lange-Nielsen syndrome (JLNS) comprises profound congenital sensorineural deafness associated with syncopal episodes. These are caused by ventricular arrhythmias secondary to abnormal repolarisation, manifested by a prolonged QT interval on the electrocardiogram. Recently, in families with JLNS, Neyroud et al. reported homozygosity for a single mutation in KVLQT1 , a gene which has previously been shown to be mutated in families with dominantly inherited isolated long QT syndrome [Neyroud et al . (1997) Nature Genet ., 15, 186-189]. We have analysed a group of families with JLNS and shown that the majority are consistent with mutation at this locus: five families of differing ethnic backgrounds were homozygous by descent for markers close to the KVLQT1 gene and a further three families from the same geographical region were shown to be homozygous for a common haplotype and to have the same homozygous mutation of the KVLQT1 gene. However, analysis of a single small consanguineous family excluded linkage to the KVLQT1 gene, establishing genetic heterogeneity in JLNS. The affected children in this family were homozygous by descent for markers on chromosome 21, in a region containing the gene IsK . This codes for a transmembrane protein known to associate with KVLQT1 to form the slow component of the delayed rectifier potassium channel. Sequencing of the affected boys showed a homozygous mutation, demonstrating that mutation in the IsK gene may be a rare cause of JLNS and that an indistinguishable phenotype can arise from mutations in either of the two interacting molecules.

Chromosomes, Human, Pair 21↗
PubMed1997

The oral-facial-digital syndrome type 1 (OFD1), a cause of polycystic kidney disease and associated malformations, maps to Xp22.2-Xp22.3.

Key features of the oral-facial-digital syndrome type 1 (OFD1) include malformations of the face, oral cavity and digits. In addition, the clinical phenotype often includes mental retardation and renal functional impairment. Approximately 75% of cases of OFD1 are sporadic, and the condition occurs almost exclusively in females. In familial cases, the most likely mode of inheritance is considered to be X-linked dominant with prenatal lethality in affected males. Therefore, the OFD1 gene product appears to have widespread importance in organogenesis and is essential for fetal survival. We have studied two kindreds in which the clinical course was dominated by polycystic kidney disease requiring dialysis and transplantation. Using polymorphic chromosome markers spaced at approximately 10 cM intervals along the X chromosome, we mapped the disease to a region on the short arm of the X chromosome (Xp22.2-Xp22.3) spanning 19.8 cM and flanked by crossovers with the markers DXS996 and DX7S105. There was a maximum lod score of 3.32 in an 'affecteds only' analysis using a marker within the KAL gene (theta = 0.0 ), thereby confirming the location of the gene for OFD1 on the X chromosome. The remainder of the X chromosome was excluded by recombinants in affected individuals. The importance of our findings includes the definitive assignment of this male-lethal disease to the X chromosome and the mapping of a further locus for a human polycystic kidney disease. Furthermore, this mapping study suggests a possible mouse model for OFD1 as the X-linked dominant Xpl mutant, in which polydactyly and renal cystic disease occurs, maps to the homologous region of the mouse X chromosome.

Chromosome Aberrations↗
PubMed1997

The TWIST gene, although not disrupted in Saethre-Chotzen patients with apparently balanced translocations of 7p21, is mutated in familial and sporadic cases.

The TWIST gene maps to 7p21 and mutations in the gene have been reported in the Saethre-Chotzen form of craniosynostosis. The position of the Saethre-Chotzen gene has previously been refined by FISH analysis of four patients carrying balanced translocations involving 7p21 which suggested that it was located between D7S488 and D7S503. We report here that the breakpoints in four translocation patients do not interrupt the coding sequence of the TWIST gene and thus most likely act through a positional effect. Twelve Saethre-Chotzen cases were found to have TWIST mutations. Four of these families had been used as part of the linkage study of the Saethre-Chotzen locus. The mutations detected included missense and nonsense mutations and three cases of a 21 bp duplication. Although phenotypically diagnosed as having Saethre-Chotzen syndrome, three families were found to have a pro250arg mutation of FGFR3.

Acrocephalosyndactylia↗
PubMed1997

Craniosynostosis associated with FGFR3 pro250arg mutation results in a range of clinical presentations including unisutural sporadic craniosynostosis.

Several mutations involving the fibroblast growth factor receptor (FGFR) gene family have been identified in association with phenotypically distinct forms of craniosynostosis. One such point mutation, resulting in the substitution of proline by arginine in a critical region of the linker region between the first and second immunoglobulin-like domains, is associated with highly specific phenotypic consequences in that mutation at this point in FGFR1 results in Pfeiffer syndrome and analogous mutation in FGFR2 results in Apert syndrome. We now show that a much more variable clinical presentation accompanies analogous mutation in the FGFR3 gene. Specifically, mental retardation, apparently unrelated to the management of the craniosynostosis, appears to be a variable clinical consequence of this FGFR3 mutation.

Acrocephalosyndactylia↗
PubMed1997

Counselling dilemmas associated with the molecular characterisation of two Angelman syndrome families.

We report the molecular characterisation of two families with Angelman syndrome referred for prenatal diagnosis, in which atypical molecular findings resulted in counselling dilemmas. The first is a familial case of Angelman syndrome in which the two affected children have mutations which affect the imprinting mechanism, as shown by the presence of paternal DNA methylation patterns at D15S63 and SNRPN and biparental inheritance of 15q11-q13 markers. DNA prepared from a 21 week fetal blood sample detected a fetus with normal maternal and paternal DNA methylation patterns at D15S63, but inheritance of the same maternal chromosome 15q11-q13 as the two affected sibs. This is probably a result of germline mosaicism in the mother. The second is a case of Angelman syndrome with an atypical deletion of 15q11-q13, which involves both unusual proximal and distal breakpoints. The deletion was characterised in order to assess the risk of Angelman syndrome in a second pregnancy in the mother of this child.

Angelman Syndrome↗
PubMed1997

Clinical-neurologic, cytogenetic and molecular aspects of the Prader-Willi and Angelman syndromes.

The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are human neurogenetic disorders involving the imprinting mechanism, at the 15q11-13 chromosome region. The predominant genetic defects in PW are 15q11-13 deletions of paternal origin and maternal chromosome 15 uniparental disomy. In contrast, maternal deletions and paternal chromosome 15 uniparental disomy are associated with a different neurogenetic disorder, the AS. In both disorders, these mutations are associated with parent-of-origin specific methylation at several 15q11-13 loci. We studied 5 patients suspect of PWS and 4 patients suspect of AS who were referred to the Medical Genetics Unit at the University Hospital of Medical School from Ribeirão Preto. Our objective was to establish the correct clinical and etiological diagnosis in these cases. We used conventional cytogenetics, methylation analysis with the probe KB17 (CpG island of the SNRPN gene) by Southern blotting after digestion with the Xba I and Not I restriction enzymes. We studied in patients and their parents the segregation of the (CA)*** repeats polymorphisms by PCR, using the primers 196 and IR4-3R. All the patients had normal conventional cytogenetical analysis. We confirmed 3 cases of PWS: one by de novo deletion, one by maternal chromosome 15 uniparental disomy and one case with no defined cause determined by the used primers. We confirmed 2 cases of AS, caused by de novo deletion at the 15q11-13 region, and one case with normal molecular analysis but with strong clinical characteristics.

Adolescent↗
PubMed1996

Minimal definition of the imprinting center and fixation of chromosome 15q11-q13 epigenotype by imprinting mutations.

Patients with disorders involving imprinted genes such as Angelman syndrome (AS) and Prader-Willi syndrome (PWS) can have a mutation in the imprinting mechanism. Previously, we identified an imprinting center (IC) within chromosome 15q11-ql3 and proposed that IC mutations block resetting of the imprint, fixing on that chromosome the parental imprint (epigenotype) on which the mutation arose. We now describe four new microdeletions of the IC, the smallest (6 kb) of which currently defines the minimal region sufficient to confer an AS imprinting mutation. The AS deletions all overlap this minimal region, centromeric to the PWS microdeletions, which include the first exon of the SNRPN gene. None of five genes or transcripts in the 1.0 Mb vicinity of the IC (ZNF127, SNRPN, PAR-5, IPW, and PAR-1), each normally expressed only from the paternal allele, was expressed in cells from PWS imprinting mutation patients. In contrast, AS imprinting mutation patients show biparental expression of SNRPN and IPW but must lack expression of the putative AS gene 250-1000 kb distal of the IC. These data strongly support a model in which the paternal chromosome of these PWS patients carries an ancestral maternal epigenotype, and the maternal chromosome of these AS patients carries an ancestral paternal epigenotype. The IC therefore functions to reset the maternal and paternal imprints throughout a 2-Mb imprinted domain within human chromosome 15q11-q13 during gametogenesis.

Angelman Syndrome↗