These six syndromes are all X-linked dominant conditions caused by mutations in the FLNA gene, which encodes Filamin A, a 280 kDa cytoskeletal protein that cross-links actin into tridimensional networks or stress-fibers in response to extracellular signals (Cunningham et al.,1992; Hartwig and Stossel,1975; Niederman et al.,1983; Tu et al.,2003). Filamin A contains an actin-binding domain located at the N-terminus, consisting of 2 calponin homology domains, and 24 filamin repeats interrupted by two hinge regions, the last one allowing homodimerization (see Fig. 1) (Robertson,2005). Filamin A can bind a vast array of proteins (Zhou et al.,2007), that modulate its multiple cellular functions. The most recognized is its ability to reorganize the actin cytoskeleton by binding to the β-chain of integrins (Zhou et al.,2010), which allows Filamin A to control cell polarization and migration in some cell types (Calderwood et al.,2001; Cunningham et al.,1992; Hart et al.,2006). Filamin A can interact with small GTPases and their effectors (Zhou et al.,2010), and modulate gene transcription (Berry et al.,2005; Sasaki et al.,2001). Filamin A has been found in the podosome belt of osteoclasts (Marzia et al.,2006) and in invadopodia of invasive and non-invasive oral squamous carcinoma cell lines (Takkunen et al.,2010). The exact role of Filamin A in invadopodia and podosome formation or function has not been explored yet.
The 6 hereditary diseases caused by mutations in the FLNA gene are very different in their clinical manifestations. PVNH is a neuronal migration disorder caused by mutations of the FLNA gene that cause loss-of-function of the protein (Fox et al.,1998). The most common manifestation of PVNH is seizures that usually start during adolescence. Other complications affect the vascular system, and include patent ductus arteriosus and coagulopathy. PVNH is lethal in males, who usually die early in gestation (Eksioglu et al.,1996), indicating the importance of Filamin A in embryogenesis. Analysis of mice deficient for Filamin A supports this finding. Male mice null for Filamin A die at E14.5 and present hemorrhage and edema. Analysis of the embryos revealed abnormal vascular patterning and severe cardiac defects involving atria, ventricles and the outflow tract. Surprisingly, migration of mutant neural crest cells in vivo and murine embryonic fibroblasts in vitro was not impaired, and the null brains appeared to develop normally (Feng et al.,2006). In a different loss-of-function mutant FLNA mouse model, unfused sternum and cleft palate were described in addition to the other phenotypes (Hart et al.,2006). In keeping with the effects of Filamin A on heart development, mutations in FLNA have recently been identified as the cause of XMVD (Kyndt et al.,2007). Myxomatous dystrophies are characterized by excessive valve tissue that leads to swelling of the valve leaflets, with or without valve prolapse and regurgitation, the most typical form being mitral valve prolapse (Levy and Savage,1987). XMVD has variable severity among carriers, and has complete penetrance in men and incomplete penetrance in women.
The otopalatodigital spectrum syndromes—OPD1, FMD, OPD2, and MNS—are caused by mutations in the FLNA gene that create gain-of-function changes without disturbing the length of the protein (Clark et al.,2009; Robertson,2007; Robertson et al.,2003). These four syndromes cause similar anomalies—craniofacial, skeletal, heart, genitourinary, and intestinal tracts dysplasias—but differ in their severity, being OPD1 the mildest and MNS the most serious of the spectrum (Tables 2 and 3). OPD1 is characterized by cleft palate, occipital, frontal, and supraorbital prominence, flat nasal root, hypertelorism, dental anomalies, and small mouth. Skeletal anomalies include short stature, digital, and sternum deformities, mild bowing of long bones and deafness due to malformations of the auditory ossicles (Dudding et al.,1967; Gall et al.,1972; Hidalgo-Bravo et al.,2005). Females present a milder form of the phenotypes than males, although occasionally can be as affected (Gorlin et al.,1973; Langer,1967). FMD patients have generalized skeletal dysplasia, characterized by bowing and flaring of bones, scoliosis, joint contractures, arachnodactyly, and deafness. They also present asthenia and urogenital defects (Fitzsimmons et al.,1982; Glass and Rosenbaum,1995; Gorlin and Cohen,1969; Kanemura et al.,1979; Morava et al.,2003). FMD craniofacial defects are characterized by increased bone density in the supraorbital area and jaw, low-set ears, bushy eyebrows, hypertelorism, dentition anomalies, and delayed fontanel closure (Fitzsimmons et al.,1982; Gorlin and Winter,1980; Morava et al.,2003). OPD2 affected males have disabling skeletal anomalies and malformations in the hindbrain, heart, intestines, and kidneys that frequently lead to death within the first year of life (Verloes et al.,2000). Craniofacial defects of OPD2 patients include large anterior fontanels, hypertelorism, prominent forehead, downslanting palpebral fissures, broad nasal bridge, low-set ears, cleft palate, small mouth, and micrognathia (Fitch et al.,1983; Fitch et al.,1976; Verloes et al.,2000). OPD2 affected females present a mild form of the craniofacial traits, but do not usually have the skeletal anomalies, and carriers can be asymptomatic (Ogata et al.,1990; Preis et al.,1994). MNS, the most serious of all four, causes malformations as severe as the ones seen in OPD2 patients, typically causing male death in utero or during the first months of life. (Donnenfeld et al.,1987; Melnick and Needles,1966; Santos et al.,2010). Some adult female patients have been reported to die from respiratory failure (Robertson,2007), but most have a normal lifespan. Craniofacial traits of the MNS comprise exophthalmos, high forehead, full cheeks, large anterior fontanel, micrognathia, and malalignment of teeth. Skeletal dysplasia is characterized by bowing of long bones with flared metaphyses, deformed clavicles, ribs, scapula, sclerosis in the base of the skull, contracted pelvis, long fingers and short stature. Analysis of affected male infants and fetuses added omphalocele, prune belly sequence, kidney hypoplasia, heart defects (tetralogy of Fallot, atrioventricular canal defect, and atrial septum malformation) and intestinal malrotation to the other traits. MNS heterozygotes present skeletal dysplasia. Curiously, some of the first FTHS patients described (ter Haar et al.,1982) were mistakenly thought to have an autosomal recessive form of MNS, due to the similar craniofacial and skeletal features present in both syndromes.
FLNA mutations associated with the OPD syndromes have been located to specific domains of Filamin A (see Fig. 1) (Robertson,2007; Robertson et al.,2003): OPD1 mutations have only been found in the second calponin homology domain of the actin-binding region, MNS mutations only in filamin repeat 10, OPD2 in the second calponin homology domain and filamin repeats 14 and 15, and FMD, in the second calponin homology domain, and repeats 3, 9, 10, 14, 15, 22, and 23.