A novel filamin A D203Y mutation in a female patient with otopalatodigital type 1 syndrome and extremely skewed X chromosome inactivation

Abstract

Otopalatodigital syndrome type 1 (OPD1) [OMIM 311300] is an X-linked dominant multiple congenital anomalies disease mainly characterized by a generalized skeletal dysplasia, mild mental retardation, hearing loss, cleft palate, and typical facial anomalies. OPD1 belongs to a group of X-linked skeletal dysplasias known as oto-palato-digital syndrome spectrum disorders that also include OPD2, Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). Recently, it has been demonstrated that mutations in the gene encoding the cytoskeletal protein Filamin A (FLNA) are responsible for this group of clinically overlapping human syndromes. We present the phenotypic and molecular data of a sporadic female patient clinically diagnosed with an OPD1 syndrome who carried a novel FLNA point mutation resulting in an Asp203Tyr substitution in the actin-binding domain of the protein. X-inactivation analyses demonstrated an extremely skewed pattern towards her maternal chromosome. Our results add to the molecular spectrum of the oto-palato-digital related syndromes and contribute to the delineation of phenotype-genotype correlation in this group of X-linked skeletal disorders.

Homocysteine Induces Hypophosphorylation of Intermediate Filaments and Reorganization of Actin Cytoskeleton in C6 Glioma Cells

“…Results are expressed as percent of controls. Statistically significant differences from controls, by one-way ANOVA followed by Tukey's multiple variation test, are indicated: * P \ 0.01 Cell Mol Neurobiol (2010) 30:557-568 565 in Charcot-Marie-Tooth disease (Zuchner et al 2005), filamin in otopalatodigital syndromes (Hidalgo-Bravo et al 2005), as well as other conditions (Lambrechts et al 2004). …”

Structural and Functional Evaluation of C. elegans Filamins FLN-1 and FLN-2

“…Human disorders such as otopalatodigital syndrome (OPD) [55], periventricular heterotopia (PVH) [56], and boomerang dysplasia (BD) [57] can be caused by mutations in the filamin ABD, which modulates the affinity of filamin for F-actin. Therefore, a greater understanding of how the actin binding activity of filamin is regulated could be clinically relevant.…”

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

“…When a disease gene is X-linked, skewed X-inactivation can cause variable penetrance of pathogenic mutations in female carriers (Van den Veyver 2001). Examples of this phenomenon involve mutations in the TIMM8A gene (Xq22.1) in dystonia-deafness syndrome (Plenge et al 1999), the EBP gene (Xp11.23) in X-linked dominant chondrodysplasia punctata (Shirahama et al 2003), the FLNA gene (Xq28) in otopalatodigital type 1 syndrome (Hidalgo-Bravo et al 2005), the ABCD1 gene (Xq28) in a family with X-linked adrenoleukodystrophy (Wang et al 2013b) and the ZIC3 gene (Xq26.3) in a family with complex heart defects (Chhin et al 2007). It should, however, be pointed out that some ZIC3 mutations are characterized by reduced penetrance in males, a finding that cannot be explained by skewed X-inactivation (Mégarbané et al 2000).…”