Biomedical subjects

R R Frants

Publications and source records attributed to R R Frants.

At least 91 records · Page 5Linked to original sources

PubMed1998

5-HT1B receptor polymorphism and clinical response to sumatriptan.

The 5-HT1 receptor agonist, sumatriptan, is highly effective in the treatment of migraine. Some patients, however, do not respond or experience recurrence of the headache. In addition, some patients report chest symptoms after sumatriptan. We investigated whether these different responses could be attributed to genetic diversity of the 5-HT1B receptor, which most likely mediates the therapeutic action and the coronary side effects of sumatriptan. Allele frequencies of two polymorphisms in the 5-HT1B receptor gene (G861C and T-261G) were investigated in migraine patients with consistently good response to sumatriptan (n = 14), with no response (n = 12), with recurrence of the headache (n = 12), with chest symptoms (n = 13), and in patients without chest symptoms (n = 27). Allele frequencies (G:0.74; C:0.26 at nt 861 and T:0.39; G:0.61 at nt -261) did not differ between patient groups, indicating that genetic diversity of the 5-HT1B receptor does not seem to be involved in the different clinical responses to sumatriptan.

Adult↗

PubMed1998

Clinical and genetic analysis of a large Dutch family with autosomal dominant vascular retinopathy, migraine and Raynaud's phenomenon.

We describe an extended Dutch family with a new hereditary disorder: autosomal dominant vascular retinopathy, migraine and Raynaud's phenomenon. Information was obtained on 289 family members (151 males, 138 females), of whom 198 were personally interviewed. Retinopathy was found in 20 (6.9%) of the family members, migraine in 65 (22.5%) and Raynaud's phenomenon in 50 (17.3%). A combination of all three symptoms was found in 11 subjects. In a genetic linkage analysis we firstly excluded several candidate loci. Subsequently, 75% of the autosomal genome was excluded in a genome-wide search. The following conclusions were drawn. First, genetic factors are involved in Raynaud's phenomenon. Secondly, the genetic linkage of migraine with vascular retinopathy and Raynaud's phenomenon supports a vascular aetiology of this disorder. Finding the gene for this family may help to elucidate the genetic background of migraine and of vascular disorders in general.

Adolescent↗

PubMed1998

Inter- and intrachromosomal sub-telomeric rearrangements on 4q35: implications for facioscapulohumeral muscular dystrophy (FSHD) aetiology and diagnosis.

The autosomal dominant myopathy facioscapulohumeral muscular dystrophy (FSHD) is causally related to a short Eco RI fragment detected by probe p13E-11. This remnant fragment is the result of a deletion of an integral number of tandemly arrayed 3.3 kb repeat units (D4Z4) on 4q35. Despite intensive efforts, no transcribed sequences have been identified within this array. Previously, we have shown that these repeats on 4q35 have been exchanged for a similar highly homologous repeat locus on 10q26 in 20% of the population and that a short chromosome 10-like array on 4q35 also results in FSHD. Here, we describe the hybrid structure of some of these repeat arrays, reflecting additional sub-telomeric instability. In three healthy individuals carrying a 4-like repeat on chromosome 10 or vice versa, one repeat array was shown to consist of hybrid clusters of 4-derived and 10-derived repeat units. Moreover, employing pulsed field gel electrophoresis analysis, we identified two unrelated individuals carrying deletions of a chromosomal segment (p13E-11) proximal to the repeat locus. These deletions were not associated with FSHD. In one of these cases, however, an expansion of the deletion into the repeat array was observed in one of his children suffering from FSHD. These data provide additional evidence for instability of this sub-telomeric region and suggests that the length of the repeat, and not its intrinsic properties, is crucial to FSHD. Moreover, they are in agreement with the hypothesis that FSHD is caused by a position effect in which the repeat structure influences the expression of genes nearby. Therefore, the region deleted proximal to the repeat locus in healthy individuals can be instrumental to refine the critical region for FSHD1.

Chromosome Mapping↗

PubMed1998

Variable clinical expression of mutations in the P/Q-type calcium channel gene in familial hemiplegic migraine. Dutch Migraine Genetics Research Group.

Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of migraine with aura, with half of the families being assigned to chromosome 19p13. We identified missense mutations in a brain-specific calcium channel alpha1A-subunit (CACNA1A) gene on 19p13 segregating with FHM and truncating mutations in families with episodic ataxia type 2 (EA-2). Expansions of an intragenic CAG repeat have been shown in autosomal dominant cerebellar ataxia (SCA6). Hence, FHM, EA-2, and SCA6 are allelic ion channel disorders. We analyzed the phenotype-genotype relation in three unrelated FHM families with the calcium channel alpha1A-subunit gene mutations I1811L (two families) and V714A (one family). We found mutations in all but three patients with FHM (i.e., three phenocopies). In addition, the I1811L mutation occurred in two patients with "nonhemiplegic" migraine and in one subject without migraine. Cerebellar ataxia was found in both families with the I1811L mutation but not in the family with the V714A mutation. We failed to find expansions of the intragenic CAG repeat in FHM patients with cerebellar ataxia. We conclude that the I1811L mutation causes both FHM and cerebellar ataxia independent of the number of CAG repeats. The I1811L mutation may also occur in "normal" migraine patients, supporting the hypothesis that FHM is part of the migraine spectrum.

Adolescent↗

PubMed1998

Genetics and pathology of voltage-gated Ca2+ channels.

Neurotransmitter release, neuronal excitation, and a whole variety of other neuronal functions are controlled by the intra/extra cellular Ca2+ gradient. The major pathway for entry of Ca2+ into the excitable cells is mediated by voltage-gated Ca2+ channels. Several functional subclasses of voltage-dependent Ca2+ channels have been identified, based on their pharmacological, biophysical properties, and molecular cloning. Recently, three human diseases (familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia 6) were added to the growing list of ion-channel disorders, all caused by different mutations in the P/Q-type Ca2+ channel alpha 1 subunit. Molecular analysis of the Ca2+ channelopathies will provide new insights into the role, function and pathology of these voltage-gated Ca2+ channels.

Animals↗

PubMed1998

Genetics of familial atypical multiple mole-melanoma (FAMMM) syndrome in The Netherlands: how far have we come?

By the genetic localization of the first melanoma susceptibility gene on chromosome 1p we thought that the puzzle on familial melanoma families would soon be solved. Now, almost fifteen years later we have learned that inherited melanoma is not a simple genetic disorder and that multiple genes, modifying genes and environmental factors might be involved. This paper outlines the current understanding of the genetics of melanoma and the relationship to atypical nevi based on more than ten years of genetic analysis in the Dutch familial atypical multiple mole-melanoma (FAMMM) syndrome families.

Chromosomes, Human, Pair 1↗

PubMed1997

Reduced very-low-density lipoprotein fractional catabolic rate in apolipoprotein C1-deficient mice.

The function of apolipoprotein (apo) C1 in vivo is not clearly defined. Because transgenic mice overexpressing human apoC1 show elevated triacylglycerol (TG) levels [Simonet, Bucay, Pitas, Lauer and Taylor (1991) J. Biol. Chem. 266, 8651-8654], an as yet unknown role for apoC1 in TG metabolism has been suggested. Here we investigated directly the effect of the complete absence of apoC1 on very-low-density lipoprotein (VLDL)-TG lipolysis, clearance and production, by performing studies with the previously generated apoC1-deficient mice. On a sucrose-rich, low fat/low cholesterol (LFC) diet, apoC1-deficient mice accumulate in their circulation VLDL particles, which contain relatively lower amounts of lipids when compared with VLDL isolated from control mice. Lipolysis assays in vitro on VLDL from apoC1-deficient and control mice showed no differences in apparent K(m) and Vmax values (0.27 +/- 0.06 versus 0.24 +/- 0.03 mmol of TG/litre and 0.40 +/- 0.03 versus 0.36 +/- 0.03 mmol of non-esterified fatty acid (NEFA)/min per litre respectively). To correct for potential differences in the size of the VLDL particles, the resulting K(m) values were also expressed relative to apoB concentration. Under these conditions apoC1-deficient VLDL displayed a lower, but not significant, K(m) value when compared with control VLDL (3.44 +/- 0.71 versus 4.44 +/- 0.52 mmol of TG2/g apoB per litre). VLDL turnover studies with autologous injections of [3H]TG-VLDL in vivo showed that the VLDL fractional catabolic rate (FCR) was decreased by up to 50% in the apoC1-deficient mice when compared with control mice (10.5 +/- 3.4 versus 21.0 +/- 1.2/h of pool TG). No significant differences between apoC1-deficient and control mice were observed in the hepatic VLDL production estimated by Triton WR139 injections (0.19 +/- 0.02 versus 0.21 +/- 0.05 mmol/h of TG per kg) and in the extra-hepatic lipolysis of VLDL-TG (4.99 +/- 1.62 versus 3.46 +/- 1.52/h of pool TG) in vivo. Furthermore, [125I]VLDL-apoB turnover experiments in vivo also showed a 50% decrease in the FCR of VLDL in apoC1-deficient mice when compared with control mice on the LFC diet (1.1 +/- 0.3 versus 2.1 +/- 0.1/h of pool apoB). When mice were fed a very high fat/high cholesterol (HFC) diet, the VLDL-apoB FCR was further decreased in apoC1-deficient mice (0.4 +/- 0.1 versus 1.4 +/- 0.4/h of pool apoB). We conclude that, in apoC1-deficient mice, the FCR of VLDL is reduced because of impaired uptake of VLDL remnants by hepatic receptors, whereas the production and lipolysis of VLDL-TG is not affected.

Animals↗

PubMed1997

The mouse homolog of FRG1, a candidate gene for FSHD, maps proximal to the myodystrophy mutation on chromosome 8.

The human autosomal dominant neuromuscular disorder facioscapulohumeral muscular dystrophy (FSHD) is associated with deletions within a complex tandem DNA repeat (D4Z4) on Chromosome (Chr) 4q35. The molecular mechanism underlying this association of FSHD with DNA rearrangements is unknown, and, thus far, no gene has been identified within the repeat. We isolated a gene mapping 100 kb proximal to D4Z4 (FSHD Region Gene 1:FRG1), but were unable to detect any alterations in total or allele-specific mRNA levels of FRG1 in FSHD patients. Human Chr 4q35 exhibits synteny homology with the region of mouse Chr 8 containing the gene for the myodystrophy mutation (myd), a possible mouse homolog of FSHD. We report the cloning of the mouse gene (Frg1) and show that it maps to mouse Chr 8. Using a cross segregating the myd mutation and the European Collaborative Interspecific Backcross, we showed that Frg1 maps proximal to the myd locus and to the Clc3 and Ant1 genes.

Amino Acid Sequence↗

PubMed1997

Hyperekplexia-like syndromes without mutations in the GLRA1 gene.

Hyperekplexia (MIM: 149400), or startle disease, is an autosomal dominant neurological disorder characterized by an extreme generalized stiffness immediately after birth, normalizing during the first years of life. Other features of this disorder are excessive startle reactions to unexpected, particularly auditory, stimuli together with a short period of generalized stiffness during which voluntary movements are impossible. Linkage analysis mapped a gene for this disorder to chromosome 5q33-q35. Subsequently, mutations in the GLRA1 gene encoding the alpha 1-subunit of the glycine receptor proved to be causally related to the disease. In the present study, mutation analysis of all exon and flanking intron sequences of this gene was performed in sporadic patients and their parents. Moreover, a branch of the original Dutch hyperekplexia family with a very severely affected individual was screened for an additional mutation in the GLRA1 gene. Except for two polymorphisms, of which one results in an amino acid change, no potentially disease causing mutations were found in the alpha 1-subunit of the glycine receptor. Together with haplotype analysis these results exclude a recessive inheritance or new mutation etiology in these hyperekplexia-like syndrome and emphasize that hyperekplexia-like syndromes can be caused by other genetic factors. The involvement of other genes encoding subunits of the functional glycine receptor complex has not been excluded.

Adult↗

PubMed1997

Wolff Award 1997. Involvement of a Ca2+ channel gene in familial hemiplegic migraine and migraine with and without aura. Dutch Migraine Genetics Research Group.

A gene for familial hemiplegic migraine, a subtype of migraine with aura, was assigned to chromosome 19p13. In this region, we identified a brain-specific P/Q-type calcium-channel alpha 1A-subunit gene, CACNA 1A, with 47 exons covering 300 kb. Sequencing of all exons and their flanking surroundings revealed polymorphic variations, including a (CA)n-repeat and a (CAG)n-repeat in the 3' untranslated region. In patients with familial hemiplegic migraine, we found four different missense mutations in conserved functional domains. One of the mutations has occurred on two different haplotypes in unrelated familial hemiplegic migraine families. Moreover, in episodic ataxia type 2, we found two mutations disrupting the reading frame. Thus, familial hemiplegic migraine and episodic ataxia type 2 can be considered as allelic channelopathies. Involvement of this familial hemiplegic migraine locus in migraine with and without aura was demonstrated by sib-pair analysis. We showed an increase of shared marker alleles of locus D19S394, which is tightly linked to the gene. The association between the alpha 1A calcium channel and familial hemiplegic migraine, and the increase of shared alleles in migraine-affected sib-pairs, have uncovered a new pathway for the pathophysiology of migraine. This finding may provide a rationale for the development of specific prophylactic therapy for migraine and other (paroxysmal) cerebral disorders.

Alleles↗

PubMed1997

Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p.

Point mutations of the CACNA1A gene coding for the alpha 1A voltage-dependent calcium channel subunit are responsible for familial hemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). In addition, expansions of the CAG repeat motif at the 3' end of the gene, smaller than those responsible for dynamic mutation disorders, were found in patients with a progressive spinocerebellar ataxia, named SCA6. In the present work, the analysis of two new families with small CAG expansions of the CACNA1A gene is presented. In one family, with a clinical diagnosis of EA2, a CAG23 repeat allele segregated in patients showing different interictal symptoms, ranging from nystagmus only to severe progressive cerebellar ataxia. No additional mutations in coding and intron-exon junction sequences in disequilibrium with the CAG expansion were found. In the second family, initially classified as autosomal dominant cerebellar ataxia of unknown type, an inter-generational allele size change showed that a CAG20 allele was associated with an EA2 phenotype and a CAG25 allele with progressive cerebellar ataxia. These results show that EA2 and SCA6 are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggest that the small expansions may not be as stable as previously reported. A refinement of the coding and intron-exon junction sequences of the CACNA1A gene is also provided.

Adolescent↗

PubMed1997

The quest for migraine genes.

Research into the genetics of migraine remains difficult because of the involvement of polygenetic and environmental factors. The discovery of the gene for familial hemiplegic migraine on chromosome 19p 13 is an important step forward. This brain specific P/Q-type calcium channel alpha 1-subunit gene opens new avenues for studying the genetics of migraine, the pathophysiology of the onset of migraine attacks and the development of novel specific prophylactic drugs.

Family Health↗

PubMed1997

Partial cosegregation of familial hemiplegic migraine and a benign familial infantile epileptic syndrome.

PURPOSE: We studied a large Dutch-Canadian family, in which two very rare hereditary paroxysmal neurologic disorders, familial hemiplegic migraine (FHM) and a "benign familial infantile epileptic syndrome" concur and partially cosegregate. FHM is a dominantly inherited subtype of migraine with attacks of hemiparesis, linked to chromosome 19p13 in 50% of the families tested. Recently mutations in a brain-specific P/Q-type Ca2+ channel alpha1 subunit gene (CACNL1A4) were identified in families with chromosome 19-linked FHM. The infantile epileptic syndrome resembles to two other dominantly inherited benign epilepsies occurring in the first year of life, benign familial neonatal convulsions (BFNC), assigned to chromosomes 20q13.2 and 8q, and benign infantile familial convulsions (BIFC), as yet unlinked. METHODS: Linkage analysis was performed for the known locations of FHM and BFNC. The question whether the two conditions in this family can be caused by a single gene defect was addressed by additional linkage analysis. RESULTS: We excluded linkage of the infantile convulsions to markers on chromosome 20q13.2, 8q, or 19p13. This indicates the existence of a third locus for benign familial convulsions in the first year of life. Linkage of FHM to these markers was not formally excluded but seems very unlikely. Statistical analysis of whether, in this family, both conditions are caused by a single gene defect was inconclusive. CONCLUSIONS: We describe a "benign familial infantile epileptic syndrome" with attacks of FHM at a later age. Further genetic studies in this family may help to unravel the genetic basis of epilepsy or migraine or both.

Age of Onset↗

PubMed1997

Familial hemiplegic migraine: involvement of a calcium neuronal channel.

A gene for familial hemiplegic migraine (FHM), a subtype of migraine with aura, has been assigned to chromosome 19p13. In this region we identified a brain-specific P/Q-type calcium channel alpha 1A-subunit gene, CACNL1A4, with 47 exons covering 300 kb. Sequencing of all exons and their flanking surroundings revealed polymorphic variations, including a (CA)n-repeat, and a (CAG)n-repeat in the 3'-UTR. In FHM patients, we found four different missense mutations in conserved functional domains. One of the mutations has occurred on two different haplotypes in unrelated FHM families. Moreover, in episodic ataxia type-2 (EA-2), we found two mutations disrupting the reading frame. Thus, FHM and EA-2 can be considered as allelic channelopathies. Involvement of this FHM locus in migraine with and without aura was demonstrated by sib-pair analysis. We showed an increase of shared marker alleles of locus D19S394, which is tightly linked to the gene. The association between the alpha 1A calcium channel and FHM, and the increase of shared alleles in migraine affected sib-pairs, have uncovered a new pathway for the pathophysiology of migraine. This finding may provide a rationale for the development of specific prophylactic therapy for migraine and other (paroxysmal) cerebral disorders.

Calcium Channels↗

PubMed1996

Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.

Genes for familial hemiplegic migraine (FHM) and episodic ataxia type-2 (EA-2) have been mapped to chromosome 19p13. We characterized a brain-specific P/Q-type Ca2+ channel alpha1-subunit gene, CACNL1A4, covering 300 kb with 47 exons. Sequencing of all exons and their surroundings revealed polymorphic variations, including a (CA)n-repeat (D19S1150), a (CAG)n-repeat in the 3'-UTR, and different types of deleterious mutations in FHM and EA-2. In FHM, we found four different missense mutations in conserved functional domains. One mutation has occurred on two different haplotypes in unrelated FHM families. In EA-2, we found two mutations disrupting the reading frame. Thus, FHM and EA-2 can be considered as allelic channelopathies. A similar etiology may be involved in common types of migraine.

Base Sequence↗

PubMed1996

Effect of apolipoprotein E and insulin resistance on VLDL particles in combined hyperlipidemic patients.

Apolipoprotein (apo) E2 and high insulin levels are associated with the severity of hypertriglyceridemia in patients with combined hyperlipidemia. To study how these determinants affect very low-density lipoprotein (VLDL) in combined hyperlipidemic patients, we characterized VLDL particles in 106 unrelated patients with combined hyperlipidemia. The study was performed after 9 weeks of standardized dietary intake and after an overnight fast. Patients heterozygous for apoE2 had significantly higher mean levels of VLDL cholesterol by 0.71 mmol/l (95% CI, 0.30 to 1.12 mmol/l, P < 0.005) and VLDL triglycerides by 0.88 mmol/l, (95% CI, 0.30 to 1.47 mmol/l, P < 0.005) compared to patients without apoE2. The VLDL triglyceride content per particle and the calculated diameter of the VLDL particles were similar in both groups, which indicate a higher number of circulating VLDL particles in heterozygous apoE2 carriers. Patients with high fasting insulin levels (> or = 80 pmol/l) had a higher mean serum VLDL triglyceride level by 0.56 mmol/l (95% CI, 0.04 to 1.07 mmol/l, P < 0.05). The calculated VLDL diameter was larger by 3.7 nm (95% CI, 1.2 to 6.2 nm, P < 0.005) and the particles contained more triglycerides by 2.7 weight percent (95% CI, 0.3 to 5.1 weight percent, P < 0.05). These insulin-dependent changes in VLDL particles were only present in the absence of apoE2. In conclusion, patients heterozygous for apoE2 have higher numbers of circulating VLDL particles, whereas patients with high fasting insulin levels have larger, triglyceride enriched VLDL particles.

Adult↗

PubMed1996

Apolipoprotein E1-Hammersmith (Lys146-->Asn;Arg147-->Trp), due to a dinucleotide substitution, is associated with early manifestation of dominant type III hyperlipoproteinaemia.

Apolipoprotein E (apoE) is one of the major protein constituents of chylomicron and very low density lipoprotein (VLDL) remnants and plays a central role as a ligand in the receptor-mediated uptake of these particles by the liver. Here we describe a new variant of apoE, apoE1-Hammersmith, which is associated with dominantly expressed type III hyperlipidaemia. The propositus, aged 26, developed tubero-eruptive xanthomas at the age of 3, her daughter developed similar lesions at age 7 but her son, aged 3, shows no clinical abnormality so far. All three cases had an apoE3E1 phenotype and a broad beta band on lipoprotein electrophoresis. Cysteamine modification resulted in a shift of apoE1 to the apoE2 isoform position, indicating that the mutation leading to apoE1-Hammersmith occurred on an apoE3 background. ApoE genotyping confirmed these results. Sequence analysis of DNA of the propositus was performed for exons 3 and 4 and revealed a dinucleotide substitution causing two amino acid changes at adjacent positions (Lys146-->Asn) and (Arg147-->Trp).

Adult↗

PubMed1996

Modulation of very low density lipoprotein production and clearance contributes to age- and gender- dependent hyperlipoproteinemia in apolipoprotein E3-Leiden transgenic mice.

Apolipoprotein E3-Leiden (APOE*3-Leiden) transgenic mice have been studied to identify factors modulating chylomicron and VLDL remnant lipoprotein metabolism. Transient elevated levels of VLDL/LDL-sized lipoproteins occurred in these mice with maximal levels during the period of rapid growth (optimum at 45 d of age). After about 100 d of age, serum cholesterol and triglyceride levels stabilized to slightly elevated levels as compared to control mice. The expression of the APOE*3-Leiden transgene was not age-dependent. In young mice the in vivo hepatic production of VLDL-triglycerides was 50% increased as compared to older mice. This is sustained by in vivo VLDL-apo B turnover studies showing increased (75%) VLDL-apo B secretion rates in young mice, whereas the VLDL-apo B clearance rate appeared not to be age dependent. On a high fat/cholesterol diet, females displayed significantly higher cholesterol levels than males (10 versus 7.0 mmol/liter, respectively). Serum levels of VLDL/LDL sized lipoproteins increased upon administration of estrogens, whereas administration of testosterone gave the opposite result. As compared to male mice, in female mice the hepatic VLDL-triglyceride production rate was significantly elevated. Injection of estrogen in males also resulted in increased VLDL-triglyceride production, although not statistically significant. In vivo VLDL-apo B turnover experiments showed that the VLDL secretion rate tended to be higher in females. Although, the fractional catabolic rate of VLDL-apo B is not different between males and females, administration of estrogens in males resulted in a decreased clearance rate of VLDL, whereas administration of testosterone in females resulted in an increased clearance rate of VLDL. The latter presumably due to an inhibiting effect of testosterone on the expression of the APOE*3-Leiden transgene. We conclude that hyperlipidemia in APOE*3-Leiden transgenic mice is strongly affected by age via its effect on hepatic VLDL production rate, whereas gender influences hyperlipidemia by modulating both hepatic VLDL production and clearance rate.

Age Factors↗