Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations conferring loss of function at the FLNA (encoding filamin A) locus lead to X-linked periventricular nodular heterotopia (XL-PH), with seizures constituting the most common clinical manifestation of this disorder in female heterozygotes. Vascular dilatation (mainly the aorta), joint hypermobility and variable skin findings are also associated anomalies, with some reports suggesting that this might represents a separate syndrome allelic to XL-PH, termed as Ehlers-Danlos syndrome-periventricular heterotopia variant (EDS-PH). Here, we report a cohort of 11 males and females with both hypomorphic and null mutations in FLNA that manifest a wide spectrum of connective tissue and vascular anomalies. The spectrum of cutaneous defects was broader than previously described and is inconsistent with a specific type of EDS. We also extend the range of vascular anomalies associated with XL-PH to included peripheral arterial dilatation and atresia. Based on these observations, we suggest that there is little molecular or clinical justification for considering EDS-PH as a separate entity from XL-PH, but instead propose that there is a spectrum of vascular and connective tissues anomalies associated with this condition for which all individuals with loss-of-function mutations in FLNA should be evaluated. In addition, since some patients with XL-PH can present primarily with a joint hypermobility syndrome, we propose that screening for cardiovascular manifestations should be offered to those patients when there are associated seizures or an X-linked pattern of inheritance.
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PMID:Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A. 2303 11

Mutations in FLNA (Filamin A, OMIM 300017) cause X-linked periventricular nodular heterotopia (XL-PNH). XL-PNH-associated mutations are considered lethal in hemizygous males. However, a few males with unusual mutations (including distal truncating and hypomorphic missense mutations), and somatic mosaicism have been reported to survive past infancy. Two brothers had an atypical presentation with failure to thrive and distinct facial appearance including hypertelorism. Evaluations of these brothers and their affected cousin showed systemic involvement including severe intestinal malfunction, malrotation, congenital short bowel, PNH, pyloric stenosis, wandering spleen, patent ductus arteriosus, atrial septal defect, inguinal hernia, and vesicoureteral reflux. The unanticipated finding of PNH led to FLNA testing and subsequent identification of a novel no-stop FLNA mutation (c.7941_7942delCT, p.(*2648Serext*100)). Western blotting and qRT-PCR of patients' fibroblasts showed diminished levels of protein and mRNA. This FLNA mutation, the most distal reported so far, causes in females classical XL-PNH, but in males an unusual, multi-organ phenotype, providing a unique insight into the FLNA-associated phenotypes.
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PMID:Novel no-stop FLNA mutation causes multi-organ involvement in males. 2387 1

Peters anomaly is a rare form of anterior segment ocular dysgenesis, which can also be associated with additional systemic defects. At this time, the majority of cases of Peters anomaly lack a genetic diagnosis. We performed whole exome sequencing of 27 patients with syndromic or isolated Peters anomaly to search for pathogenic mutations in currently known ocular genes. Among the eight previously recognized Peters anomaly genes, we identified a de novo missense mutation in PAX6, c.155G>A, p.(Cys52Tyr), in one patient. Analysis of 691 additional genes currently associated with a different ocular phenotype identified a heterozygous splicing mutation c.1025+2T>A in TFAP2A, a de novo heterozygous nonsense mutation c.715C>T, p.(Gln239*) in HCCS, a hemizygous mutation c.385G>A, p.(Glu129Lys) in NDP, a hemizygous mutation c.3446C>T, p.(Pro1149Leu) in FLNA, and compound heterozygous mutations c.1422T>A, p.(Tyr474*) and c.2544G>A, p.(Met848Ile) in SLC4A11; all mutations, except for the FLNA and SLC4A11 c.2544G>A alleles, are novel. This is the first study to use whole exome sequencing to discern the genetic etiology of a large cohort of patients with syndromic or isolated Peters anomaly. We report five new genes associated with this condition and suggest screening of TFAP2A and FLNA in patients with Peters anomaly and relevant syndromic features and HCCS, NDP and SLC4A11 in patients with isolated Peters anomaly.
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PMID:Whole exome sequence analysis of Peters anomaly. 2518 19

Mutations of FLNA, an X-linked gene that encodes the cytoskeletal protein filamin A, cause diverse and distinct phenotypes including periventricular nodular heterotopia and otopalatodigital spectrum disorders (OPDS). Craniofacial abnormalities associated with OPDS include supraorbital hyperostosis, down-slanting palpebral fissures and micrognathia; craniosynostosis was previously described in association with FLNA mutations in two individual case reports. Here we present four further OPDS subjects who have pathological FLNA variants and craniosynostosis, supporting a causal link. Together with the previously reported patients, frontometaphyseal dysplasia was the most common clinical diagnosis (four of six cases overall); five patients had multiple suture synostosis with the sagittal suture being the most frequently involved (also five patients). No genotype-phenotype correlation was evident in the distribution of FLNA mutations. This report highlights the need to consider a filaminopathy in the differential diagnosis of craniosynostosis, especially in the presence of atypical cranial or skeletal features.
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PMID:Association of mutations in FLNA with craniosynostosis. 2587 11

Frontometaphyseal dysplasia (FMD) is a distinctive sclerosing skeletal dysplasia associated with a number of non-skeletal manifestations including hearing loss, cardiac malformations, and stenosis, particularly of the upper airway and urinary tract. Some, but not all, patients have mutations in FLNA causing the condition. Consonant with the X chromosomal location of FLNA males are generally more severely affected than females. FLNA mutations can be detected in 82% of affected males. We describe seven patients (one male, six females) all of whom have the major clinical and radiological features of FMD, but without detectable mutations in FLNA. The females in our cohort are affected to a similar degree as is usually found in males. In addition, all patients have marked keloid formation at various body sites, including the eye, from an early age. Other features that may indicate a different etiology in these patients are the increased frequency of cleft palate, Robin sequence, tracheal stenosis, and mild intellectual disability, which all occur in three of more patients in the present group. All patients are isolated. We hypothesize that the presently reported patients represent further evidence that phenotypes strongly resembling FMD exist that are not accounted for by mutations in FLNA. Since the frequency of several of the manifestations, their sporadic presentations, and the presence of keloid formation differ from the X-linked form of this condition we propose de novo autosomal dominant acting mutations in a gene functionally related to FLNA, underpin this disorder.
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PMID:Frontometaphyseal dysplasia and keloid formation without FLNA mutations. 2589 17

Terminal osseous dysplasia with pigmentary defects (TODPD) is a rare, X-linked syndrome classically characterized by distal limb anomalies, pigmented skin defects of the face, and recurrent digital fibromas. X-inactivation plays a major role in determining the range of phenotypic expression. Thus, patients can demonstrate a wide spectrum of disease severity, making accurate diagnosis more challenging. Recent studies have identified a FLNA c.5217G>A mutation as the cause of TODPD, allowing for diagnostic genetic testing. We present a case of molecularly confirmed TODPD in a girl with the 47,XXX chromosomal complement and deformities of the hands and feet, craniofacial abnormalities, and discolored, linear facial lesions. Skin biopsy of the patient's facial lesion revealed absent papillary dermal elastic fibers, consistent with anetoderma, which contrasts with the dermal hypoplasia described in the only other such facial biopsy reported in the literature. The finding of absent elastic fibers in the skin lesions suggests that mutated filamin A, in part, exerts its effects through dysregulated elastin biology, which may explain the nature of many connective tissue pleotropic effects in FLNA-related disorders.
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PMID:Anetoderma in a patient with terminal osseous dysplasia with pigmentary defects. 2605 11

Congenital Short Bowel Syndrome (CSBS) is a rare gastrointestinal disorder in which the mean length of the small intestine is substantially reduced when compared to its normal counterpart. Families with several affected members have been described and CSBS has been suggested to have a genetic basis. Recently, our group found mutations in CLMP as the cause of the recessive form of CSBS, and mutations in FLNA as the cause of the X-linked form of the disease. These findings have improved the quality of genetic counselling for CSBS patients and made prenatal diagnostics possible. Moreover, they provided a reliable starting point to further investigate the pathogenesis of CSBS, and to better understand the development of the small intestine. In this review, we present our current knowledge on CSBS and discuss hypotheses on how the recent genetic findings can help understand the cause of CSBS.
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PMID:Congenital Short Bowel Syndrome: from clinical and genetic diagnosis to the molecular mechanisms involved in intestinal elongation. 2628 49

Although the genetic basis of mitral valve prolapse (MVP) has now been clearly established, the molecular and cellular mechanisms involved in the pathological processes associated to a specific mutation often remain to be determined. The FLNA gene (encoding Filamin A; FlnA) was the first gene associated to non-syndromic X-linked myxomatous valvular dystrophy, but the impacts of the mutations on its function remain un-elucidated. Here, using the first repeats (1-8) of FlnA as a bait in a yeast two-hybrid screen, we identified the tyrosine phosphatase PTPN12 (PTP-PEST) as a specific binding partner of this region of FlnA protein. In addition, using yeast two-hybrid trap assay pull down and co-immunoprecipitation experiments, we showed that the MVP-associated FlnA mutations (G288R, P637Q, H743P) abolished FlnA/PTPN12 interactions. PTPN12 is a key regulator of signaling pathways involved in cell-extracellular matrix (ECM) crosstalk, cellular responses to mechanical stress that involve integrins, focal adhesion transduction pathways, and actin cytoskeleton dynamics. Interestingly, we showed that the FlnA mutations impair the activation status of two PTPN12 substrates, the focal adhesion associated kinase Src, and the RhoA specific activating protein p190RhoGAP. Together, these data point to PTPN12/FlnA interaction and its weakening by FlnA mutations as a mechanism potentially involved in the physiopathology of FlnA-associated MVP.
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PMID:MVP-Associated Filamin A Mutations Affect FlnA-PTPN12 (PTP-PEST) Interactions. 2659 44

Human mutations in the X-linked FLNA gene are associated with a remarkably diverse phenotype, including severe arterial morphological anomalies. However, the role for filamin A (FlnA) in vascular cells remains partially understood. We used a smooth muscle (sm)-specific conditional mouse model to delete FlnA at the adult stage, thus avoiding the developmental effects of the knock-out. Inactivation of smFlnA in adult mice significantly lowered blood pressure, together with a decrease in pulse pressure. However, both the aorta and carotid arteries showed a major outward hypertrophic remodeling, resistant to losartan, and normally occurring in hypertensive conditions. Notably, arterial compliance was significantly enhanced in the absence of smFlnA. Moreover, reactivity of thoracic aorta rings to a variety of vasoconstrictors was elevated, while basal contractility in response to KCl depolarization was reduced. Enhanced reactivity to the thromboxane A2 receptor agonist U46619 was fully reversed by the ROCK inhibitor Y27632. We discuss the possibility that a reduction in arterial stiffness upon smFlnA inactivation might cause a compensatory increase in conduit artery diameter for normalization of parietal tension, independently of the ROCK pathway. In conclusion, deletion of smFlnA in adult mice recapitulates the vascular phenotype of human bilateral periventricular nodular heterotopia, culminating in aortic dilatation.
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PMID:Smooth muscle filamin A is a major determinant of conduit artery structure and function at the adult stage. 2702 51

Otopalatodigital spectrum disorders (OPDSD) constitute a group of dominant X-linked osteochondrodysplasias including four syndromes: otopalatodigital syndromes type 1 and type 2 (OPD1 and OPD2), frontometaphyseal dysplasia, and Melnick-Needles syndrome. These syndromes variably associate specific facial and extremities features, hearing loss, cleft palate, skeletal dysplasia and several malformations, and show important clinical overlap over the different entities. FLNA gain-of-function mutations were identified in these conditions. FLNA encodes filamin A, a scaffolding actin-binding protein. Here, we report phenotypic descriptions and molecular results of FLNA analysis in a large series of 27 probands hypothesized to be affected by OPDSD. We identified 11 different missense mutations in 15 unrelated probands (n=15/27, 56%), of which seven were novel, including one of unknown significance. Segregation analyses within families made possible investigating 20 additional relatives carrying a mutation. This series allows refining the phenotypic and mutational spectrum of FLNA mutations causing OPDSD, and providing suggestions to avoid the overdiagnosis of OPD1.
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PMID:Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum. 2719 21


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