Mutations in the Gene Encoding Filamin A as a Cause for Familial Cardiac Valvular Dystrophy

Abstract

Background-Myxomatous dystrophy of the cardiac valves affects Ϸ3% of the population and remains one of the most common indications for valvular surgery. Familial inheritance has been demonstrated with autosomal and X-linked transmission, but no specific molecular abnormalities have been documented in isolated nonsyndromic forms. We have investigated the genetic causes of X-linked myxomatous valvular dystrophy (XMVD) previously mapped to chromosome Xq28. Methods and Results-A familial and genealogical survey led us to expand the size of a large, previously identified family affected by XMVD and to refine the XMVD locus to a 2.5-Mb region. A standard positional cloning approach identified a P637Q mutation in the filamin A (FLNA) gene in all affected members. Two other missense mutations (G288R and V711D) and a 1944-bp genomic deletion coding for exons 16 to 19 in the FLNA gene were identified in 3 additional, smaller, unrelated families affected by valvular dystrophy, which demonstrates the responsibility of FLNA as a cause of XMVD. Among carriers of FLNA mutation, the penetrance of the disease was complete in men and incomplete in women. Female carriers could be mildly affected, and the severity of the disease was highly variable among mutation carriers. Conclusions-Our data demonstrate that FLNA is the first gene known to cause isolated nonsyndromic MVD. This is the first step to understanding the pathophysiological mechanisms of the disease and to defining pathways that may lead to valvular dystrophy. Screening for FLNA mutations could be important for families affected by XMVD to provide adequate follow-up and genetic counseling.

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

“…We could not define whether this was a benign variant rather than a really damaging mutation with incomplete penetrance as reported for females with mutation of this gene and cardiac valvular dysplasia (OMIM #314400). 37 The interpretation of the CHRNA4 mutation was also difficult as alterations of this gene can cause either nocturnal frontal lobe epilepsy type 1, although with incomplete penetrance, or nightmares and other sleep disorders that are often undiagnosed. 38 Variants in SCN1B and UBE3A were identified in the same subject.…”

A novel interaction between FlnA and Syk regulates platelet ITAM-mediated receptor signaling and function

“…Binding to FlnA Ig repeat 5 is novel, as most FlnA interacting partners bind to the C-terminal region containing Ig repeats 16-24 Feng and Walsh, 2004;Zhou et al, 2010). Mutations in FlnA Ig repeat 5 have been associated with familial cardiac valvular dystrophy (Kyndt et al, 2007). However, the consequence of these mutations on platelet activation remains to be determined, as does the location of the binding interface on Syk.…”

“…Human melanoma cells that lack FlnA have poor motility and continuous membrane blebbing (Cunningham et al, 1992;Flanagan et al, 2001). FLNA mutations have been associated with periventricular heterotopia, Ehlers-Danlos Syndrome, or familial cardiac valvular dystrophy (Fox et al, 1998;Robertson et al, 2003;Sheen et al, 2005;Kyndt et al, 2007;Unger et al, 2007). Loss of FlnA in mice results in embryonic lethality caused by pericardiac and visceral hemorrhage, severe cardiac structural defects, and aberrant vascular patterning (Feng et al, 2006;Hart et al, 2006).…”

Congenital short bowel syndrome as the presenting symptom in male patients with FLNA mutations

“…[11][12][13] Our findings add CSBS to this list as a possible presenting phenotype in male patients with a mutation in FLNA. We therefore emphasize the importance of FLNA in intestinal development.…”