Founder mutations in inherited cardiac diseases in the Netherlands


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In six patients without any obvious skin lesions, skin biopsy specimens were taken from the neck, and sections were stained by the von Kossa method. In 15 patients, recent ophthalmologic examination included visual acuity measurement, slit lamp examination, ophthalmoscopy, and often fluorescein angiography. In one patient, medical records indicated the presence of angioid streaks. In six patients, cardiovascular examinations were performed that included electrocardiograms ECGs.

Definition of ethnic origin of each subject was based on the country of birth in four generations.

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All investigations adhered to the tenets set forth by the Declaration of Helsinki. Fragments with a mobility shift in a single-strand conformational polymorphism SSCP assay were sequenced. All coding sequences were analyzed in more than healthy individuals, to distinguish between disease-causing mutations and polymorphic variants. After identification of the RX mutation and detection of other intragenic polymorphisms, optimized protocols were designed by using PCR and restriction analyses.

The RX mutation leads to the loss of a Bsi YI restriction site, which was confirmed by a restriction fragment length polymorphism assay. The Bsi YI enzyme cleaves the wild-type sequence but not the mutant sequence. Allele frequencies for identified mutations and polymorphisms were determined both in our cohort of patients with PXE and in more than control chromosomes from our healthy study participants. Haplotype Analysis and Assessment of Founder Effect. We constructed phase-known haplotypes of all informative alleles from patients with the RX mutation.

Control haplotypes were determined on the basis of the allele segregation within individual families. For functional studies, primary fibroblast cultures were established from dermal biopsy specimens of affected skin of patients with PXE and healthy control subjects.

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Total RNA was isolated from subconfluent cultures. The presence or absence of the RX mutation in individual clones was checked with digestion with Bsi YI, and, accordingly, the inserts of individual clones were assigned to be expression products from the mutant or wild-type allele. Dermal fibroblasts were seeded onto sterile glass coverslips and cultured for an additional 24 hours. This mutation produces a stop codon at instead of an arginine residue and results in a shorter mRNA and, theoretically, in a C-terminal—truncated protein that lacks part of the transmembrane domain and the second ATP-binding domain.

Previously, we found that the RX mutation was associated with a strong increase in the prevalence of coronary artery disease. A summary of the results is presented in Table 1. In three patients, the RX mutation was observed in a homozygous form; in seven, it was in heterozygous form; and in six, it occurred in combination with other mutations in the second allele in compound heterozygous form.

In three of these six compound heterozygotes from family pedigree [P], P, P , an additional intragenic When we sequenced the fragments spanning the deletion region, we found the same break points in all three patients at nucleotide within intron 22 and nucleotide within intron This seven-exon deletion is predicted to result in a polypeptide that lacks amino acids.

Dutch founder mutation in the gene for MYBPC3 is associated with a severe diseas

In the three other compound heterozygotes, the combination RX with a del22 bp in exon 16, a delT, or QX was identified. In family P, the proband showed a bp deletion in exon 16, which created a premature stop codon at position , and which resulted in the loss of eight amino acids Arg-Ile-Asn-Leu-Thr-Val-Pro-Glu [] of putative protein sequence. In family P, the proband inherited a maternal deletion of a T at cDNA position in exon 27, which resulted in a frameshift at codon and premature termination at codon To determine whether the RX mutation originates from recurrent de novo mutational events or from founder effects, ABCC6 -associated haplotypes of all patients carrying the RX mutation and of control subjects were constructed.

Characteristics and frequency of eight markers, which spanned approximately 1. We detected 11 polymorphisms in the exonic ABCC6 sequences.

Recurrent and founder mutations in inherited cardiac diseases in the Netherlands

These dimorphisms could easily be detected by PCR and restriction analysis Fig. None of 10 control subjects carried this haplotype.

To determine the effect of this mutation on the expression of the ABCC6 gene, we analyzed dermal fibroblasts from individuals homozygous or heterozygous for RX and healthy control subjects. The presence of the mutations was confirmed by PCR amplification of exon 24 containing the RX mutation followed by restriction fragment length polymorphism analysis Fig.

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To examine this in more detail, we determined the ratio of steady state transcript levels between wild-type and mutated mRNA in mononuclear blood cells and fibroblasts of patients heterozygous for the RX mutation. As a control for the latter analysis, we also determined this ratio in blood cells from a healthy donor and from a patient with PXE heterozygous for a missense mutation RC in exon 30 of ABCC6. In parallel experiments, we determined the expression of the RX truncated protein in cells of patients with PXE.

Inherited Heart Conditions

Cultured dermal fibroblasts of a patient with PXE homozygous for the RX mutation and that of a healthy control subject were analyzed by immunocytochemistry. As is shown in Figure 4 , staining with a monoclonal antibody against ABCC6 showed only staining of the control fibroblasts but not of the PXE fibroblasts.


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Incubation with a monoclonal antibody against ABCC1 indicated that this protein was expressed in both normal and PXE fibroblasts at similar levels. ABCC5 appeared not to be expressed at detectable levels by human fibroblasts, as incubation with a monoclonal antibody against this protein gave no staining above background not shown.

Phenotypes of Patients with the RX Mutation. Angioid streaks were present in 10 patients. Six patients from the latter group had neovascularization or macular degeneration. Variable cardiovascular abnormalities were detected in six patients. In summary, in all patients homozygous or compound heterozygous for the RX mutation, we observed ocular and skin abnormalities and, less frequently, cardiovascular problems.

Mijn eigen profiel maken Geciteerd door Alles weergeven Alles Sinds Citaties h-index 14 13 iindex 17 Artikelen Geciteerd door. European journal of heart failure 14 11 , , Circulation: Cardiovascular Genetics 7 4 , , The American journal of cardiology 8 , , Founder mutations in inherited cardiac diseases in the Netherlands, , The Journal of investigative dermatology 11 , , Journal of the American College of Cardiology 67 5 , , European journal of medical genetics 53 1 , , The American Journal of Human Genetics 5 , , Artikelen 1—20 Meer weergeven.

Help Privacy Voorwaarden. Circulation 23 , , Human mutation 30 9 , , KWE causes a redness of the palms and soles with consecutive cycles of peeling of large sections of thick skin, often exacerbated during winter months. Wits scientists have discovered the genetic mutation responsible for the rare skin disease, keratolytic winter erythema Oudtshoorn skin which afflicts Afrikaners.

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Afrikaners are Afrikaans-language speakers descended from predominantly Dutch, German and French settlers, who arrived in South Africa in the 17th and 18th centuries. Afrikaners have a high risk for several genetic disorders, the best known being familial hypercholesterolaemia inherited high cholesterol leading to heart attacks early in life and porphyria sensitivity of the skin to ultra-violet exposure and adverse reactions to specific drugs.

These disorders are common because of founder mutations brought to South Africa by small groups of immigrants who settled in the Cape of Good Hope and whose descendants are now spread throughout the country.


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KWE was first described as a unique and discrete skin disorder in by Wits dermatologist, Professor George Findlay.

Founder mutations in inherited cardiac diseases in the Netherlands Founder mutations in inherited cardiac diseases in the Netherlands
Founder mutations in inherited cardiac diseases in the Netherlands Founder mutations in inherited cardiac diseases in the Netherlands
Founder mutations in inherited cardiac diseases in the Netherlands Founder mutations in inherited cardiac diseases in the Netherlands
Founder mutations in inherited cardiac diseases in the Netherlands Founder mutations in inherited cardiac diseases in the Netherlands
Founder mutations in inherited cardiac diseases in the Netherlands Founder mutations in inherited cardiac diseases in the Netherlands
Founder mutations in inherited cardiac diseases in the Netherlands Founder mutations in inherited cardiac diseases in the Netherlands
Founder mutations in inherited cardiac diseases in the Netherlands Founder mutations in inherited cardiac diseases in the Netherlands
Founder mutations in inherited cardiac diseases in the Netherlands Founder mutations in inherited cardiac diseases in the Netherlands

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