Filamin A mutations responsible for X-linked cardiac myxomatous valve disease

Myxomatous degeneration of cardiac valves may occur as an isolated valvular disease or as part of a syndrome, as in Marfan syndrome.

Mitral valve prolapse, the most common degeneration, occurs in approximately 2% to 3% of the population and is the predominant reason for cardiac valvular surgery. The predominant pathology is fragmentation of collagenous bundles within the fibrosia and increased formation of proteoglycans. This can produce excess valve tissue, which leads to billowing of the valve leaflets with or without prolapse.

There is no effective treatment to alter the progressive deterioration of the valves; thus, management is primarily related to prevention of complications, which include endocarditis, until surgery is required.

Robert Roberts

Familial inheritance has been shown for mitral valve prolapse. The predominant pattern of inheritance is autosomal dominant with reduced and variable penetrance, as well as variable expressivity. Three chromosomal loci have been identified as responsible for mitral valve prolapse — 16p11-12, 11p15.4 and 13q31-32 — but none of the genes have yet been identified. An X-linked recessive form involving the mitral valve was described by Monteleone and Fagin in 1969 and Newberry-Ecob et al in 1993. In 1998, Kyndt and colleagues mapped the first chromosomal locus responsible for this disease to Xq28.

Kyndt et al have recently narrowed the locus using standard positional cloning techniques and identified a mutation in the filamin A gene. The filamin A gene consists of 48 exons that span 26,000 base pairs of DNA.

In a large family of 91 living members, a missense mutation was identified and shown to segregate with affected members. The mutation was not present in 500 normal controls. Analysis showed a C to A transition at nucleotide 1910 in exon 13. This missense mutation in the protein leads to the substitution of a proline (P) for a glutamine (Q) at amino acid 637 (P637Q).

There were 13 affected men and 30 women. In keeping with the expectation, all men with the mutation were affected since they have only one X chromosome; women, although carriers, are less likely to be affected because they initially have two X chromosomes (one X chromosome is subsequently inactivated).

Mutations in the filamin A gene were also identified in two other unrelated families. In one family there was a T to A transition at nucleotide 2132 in exon 14 which substitutes a valine (V) for aspartic acid (D) at amino acid 711 (V771D). In a third family, a 1944bp genomic deletion coding for exons 16 to 19 was discovered, which induces a 546bp coding sequence deletion giving an in-frame deletion of 182 amino acids (V761 to Q943).

Mutations in one family

Mitral valve prolapse was diagnosed using echocardiographic two-dimensional recordings in the parasternal long axis view. Patients were defined as affected if the thickness of the free edge of either or both mitral leaflets was >4 mm with or without mitral valve prolapse. Prolapse was diagnosed if mitral leaflets protruded into the left atrium, crossing the line between the annular hinge points, when the coaptation point of the leaflets remained at or above the mitral annular plane during systole.

The family consisted of four generations with 91 living members. Two of the affected men had either mitral valve replacement or valvuloplasty. The age requiring mitral surgery ranged from 20 to 51.

Prolapse was demonstrated in the anterior leaflet in four patients and in both leaflets in eight patients. All but one of the affected men had aortic valve regurgitation, which was mild in six cases, moderate in three cases and severe in three cases.

There was no abnormality of the aortic root and all aortic valves were tricuspid. The age for aortic valve surgery ranged from 17 to 52. Mild to moderate tricuspid valve regurgitation was found in 11 men and mild pulmonary regurgitation in four men.

Of the 30 heterozygous women with the mutation, none were symptomatic and none underwent valvular surgery. Fourteen women were considered affected, 12 were indeterminate and four were unaffected. Mitral valve prolapse was present in only four cases.

Filamin A is a ubiquitous phosphoprotein that plays a key role in linking the actin cytoskeleton to the plasma membrane by interacting with both actin and plasma membrane proteins, such as beta integrins. The filamin molecule has an actin-binding domain at the N-terminus and 24 homologous repeats that correspond to the rod backbone of the protein. Each repeat consists of seven anti-parallel beta strands arranged in two beta sheets. Filamins normally exist in vivo as dimmers, joined together by an interaction between the C-terminal sequences.

The mechanism whereby these mutations in filamin A induce myxomatous valvular degeneration remains unknown. However, it is well recognized that transforming growth factor beta is important in the development of cardiac valves. Mice that lack the TGF beta and bone morphogenic protein signaling inhibitor, Mothers Against Decapentaplegic Homolog 6 (SMAD 6), show hyperplasia of the cardiac valves. Thus, it is possible that filamin A may contribute to the development of myxomatous changes by regulating transforming growth factors or one of the molecules in its signaling pathways. The finding of a mutation in filamin A in three unrelated families confirms that filamin A is a major gene responsible for myxomatous degeneration of cardiac valves.

Robert Roberts, MD, is President and CEO of the University of Ottawa Heart Institute and Section Editor of the Molecular Cardiology Section of the Today in Cardiology Editorial Board.

For more information:

• Kyndt F, Gueffet JP, Probst V, et al. Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy. Circulation. 2007;115:40-49 Epub 2006; doi:10/1161/circulationaha.106.622621.