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Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenègre disease
Vincent Probst1, Florence Kyndt, Franck Potet
1Cardiology Department, Hôpital G&R Laennec, Nantes, France.
Insights
A SCN5A gene mutation causes hereditary progressive cardiac conduction defects. This condition worsens with age due to haploinsufficiency and impaired conduction velocity.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Progressive cardiac conduction defect is often linked to His bundle degeneration.
- A specific SCN5A gene splicing mutation identified in a French family causes hereditary progressive cardiac conduction defect.
Purpose of the Study:
- Investigate the genotype-to-phenotype link between SCN5A mutations and progressive cardiac conduction defects.
- Elucidate the pathophysiologic mechanisms underlying this disease.
Main Methods:
- Extended pedigree analysis, phenotyping, and genotyping of family members.
- In vitro functional studies to assess the mutation's consequences.
Main Results:
- 25 out of 65 individuals carried the IVS.22+2 T-->C SCN5A mutation.
- Gene carriers showed progressive increases in P-wave, PR, and QRS duration with age, more pronounced in those over 40.
- The mutation caused exon 22 skipping, leading to a complete loss of function but normal trafficking of the SCN5A gene product.
Conclusions:
- Hereditary Lenègre disease results from a haploinsufficiency mechanism.
- Aging exacerbates the SCN5A mutation's effect, causing progressive conduction velocity alterations.
Objectives:
The goal of this study was to investigate the genotype-to-phenotype relationship between SCN5A gene mutation and progressive cardiac conduction defect in order to gain insights into the pathophysiologic mechanisms of the disease.
Background:
Progressive cardiac conduction defect is a frequent disease commonly attributed to degeneration and fibrosis of the His bundle and its branches. In a French family, we have identified a splicing mutation in the SCN5A gene leading to hereditary progressive cardiac conduction defect.
Methods:
We have extended the size of the pedigree and phenotyped and genotyped all family members, and also investigated in vitro the functional consequences of the mutation.
Results:
Among 65 potentially affected members, 25 individuals were carriers of the IVS.22+2 T-->C SCN5A mutation. In relation to aging, gene carriers exhibit various types of conduction defects. P-wave, PR, and QRS duration increased progressively with age in gene carriers and in noncarriers. Whatever the age, conduction parameters were longer in gene carriers. The widening in the QRS complex with aging was more pronounced in gene carriers older than 40 years. Functional studies show that the IVS.22+2 T-->C SCN5A mutation lead to exon 22 skipping and to a complete loss of function of the affected allele, but to a normal trafficking of the mutated gene product.
Conclusions:
Our findings demonstrate that hereditary Lenègre disease is caused by a haploinsufficiency mechanism, which in combination with aging leads to progressive alteration in conduction velocity.