A review of filamin A mutations and associated interstitial lung disease

Sasaki, Erina; Byrne, Angela T.; Phelan, Eimear; Cox, D.; Reardon, William

doi:10.1007/s00431-018-3301-0

Cited by 54 publications

(61 citation statements)

References 20 publications

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“…Beyond the OPDSDs, FLNA variants have also been shown to cause XCVD, PVNH1 and PVNH4, childhood interstitial lung disease (ChILD), structural cardiac and aortic anomalies, thoracic aortic aneurysms (TAA), chronic intestinal pseudo-obstruction (CIPO), and congenital short bowel syndrome (CSBS) (Fig. 5a) [57,[59][60][61][62][63][64][65][66][67][68][69][70][71]. Typically, PVNH, XCVD, CIPO and CSBS are thought to be caused by LOF mutations while OPDSDs are caused by GOF FLNA mutations.…”

Section: Discussionmentioning

confidence: 99%

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

et al. 2020

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Background: Prune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically. Phenotypically, its morbidity spans from mild to lethal, however, all isolated PBS cases manifest three cardinal pathological features: 1) wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, 2) urinary tract dilation with poorly contractile smooth muscle, and 3) intra-abdominal undescended testes. Despite evidence for a genetic basis, previously reported PBS autosomal candidate genes only account for one consanguineous family and single cases. Methods: We performed whole exome sequencing (WES) of two maternal adult half-brothers with syndromic PBS (PBS + Otopalatodigital spectrum disorder [OPDSD]) and two unrelated sporadic individuals with isolated PBS and further functionally validated the identified mutations. Results: We identified three unreported hemizygous missense point mutations in the X-chromosome gene Filamin ) in two related cases and two unrelated sporadic individuals. Two of the three PBS mutations map to the highly regulatory, stretch-sensing Ig19-21 region of FLNA and enhance binding to intracellular tails of the transmembrane receptor β-integrin 1 (ITGβ1). Conclusions: FLNA is a regulatory actin-crosslinking protein that functions in smooth muscle cells as a mechanosensing molecular scaffold, transmitting force signals from the actin-myosin motor units and cytoskeleton via binding partners to the extracellular matrix. This is the first evidence for an X-linked cause of PBS in multiple unrelated individuals and expands the phenotypic spectrum associated with FLNA in males surviving even into adulthood.

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Section: Discussionmentioning

confidence: 99%

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

et al. 2020

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“…FLNA: Filamin A is an actin-binding protein that interacts with integrins, receptors, and messengers to regulate the organization of the actin cytoskeleton, which regulates motility, adhesion, and division of the cell [68]. Mutations in FLNA cause a variety of syndromes affecting the cardiovascular system (periventricular nodular heterotopia [42], X-linked cardiac valvular dysplasia [43]), osteoarticular abnormalities (Melnick-Needles syndrome, oto-palato-digital syndrome, frontometaphyseal dysplasia), or gastrointestinal disturbances [68]. Regarding the respiratory system, different articles have reported the presence of lung disease presenting hyperinsufflation and emphysematous changes in the histologic evaluation but without vascular remodeling, suggesting PAH [68].…”

Section: Genes Potentially Related To Increased Cell Proliferationmentioning

confidence: 99%

“…Mutations in FLNA cause a variety of syndromes affecting the cardiovascular system (periventricular nodular heterotopia [42], X-linked cardiac valvular dysplasia [43]), osteoarticular abnormalities (Melnick-Needles syndrome, oto-palato-digital syndrome, frontometaphyseal dysplasia), or gastrointestinal disturbances [68]. Regarding the respiratory system, different articles have reported the presence of lung disease presenting hyperinsufflation and emphysematous changes in the histologic evaluation but without vascular remodeling, suggesting PAH [68]. PAH is not a common finding in patients with genetic variants in FLNA, with only two cases described in the literature (two sisters with PAH, PAA compressing the left main coronary artery and an identified splicing mutation in the filamin A gene) [44].…”

Section: Genes Potentially Related To Increased Cell Proliferationmentioning

confidence: 99%

Potential Molecular Pathways Related to Pulmonary Artery Aneurysm Development: Lessons to Learn from the Aorta

Nuche

Palomino-Doza

Arribas

et al. 2020

IJMS

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Pulmonary arterial hypertension (PAH) is a rare disease caused by pulmonary vascular remodeling. Current vasodilator treatments have substantially improved patients' survival. This improved survival has led to the appearance of complications related to conditions previously underdiagnosed or even ignored, such as pulmonary artery aneurysm (PAA). The presence of a dilated pulmonary artery has been shown to be related to an increased risk of sudden cardiac death among PAH patients. This increased risk could be associated to the development of left main coronary artery compression or pulmonary artery dissection. Nevertheless, very little is currently known about the molecular mechanisms related to PAA. Thoracic aortic aneurysm (TAA) is a well-known condition with an increased risk of sudden death caused by acute aortic dissection. TAA may be secondary to chronic exposure to classic cardiovascular risk factors. In addition, a number of genetic variants have been shown to be related to a marked risk of TAA and dissection as part of multisystemic syndromes or isolated familial TAA. The molecular pathways implied in the development of TAA have been widely studied and described. Many of these molecular pathways are involved in the pathogenesis of PAH and could be involved in PAA. This review aims to describe all these common pathways to open new research lines that could help lead to a better understanding of the pathophysiology of PAH and PAA and their clinical implications.

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“…[14][15][16][17][18][19][20][21] A recent review summarizes the cases reported in the literature to date. 22 Thus far, at least 18 cases of FLNA-related disease with this respiratory phenotype have been identified in infancy. Most of the infants identified were girls, and respiratory symptoms developed at approximately 1 month of age.…”

Section: Connective-tissue Disordersmentioning

confidence: 99%

“…20 Since then, 17 additional case reports of lung disease have been described in the literature, but more cases are being recognized in the clinic, particularly in lung transplantation centers. [15][16][17][18][19][20][21][22]27 Of the 18 patients, 15 were female, which suggests that males are more likely to be severely affected and are less likely to survive to birth. All but 1 of these patients were born at full term.…”

Section: Agnos Tic Tes Tingmentioning

confidence: 99%

Case 28-2019: A 22-Year-Old Woman with Dyspnea and Chest Pain

et al. 2019

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A 22-year-old woman was seen in the pediatric pulmonary clinic of this hospital because of chest pain, cough, and dyspnea on exertion. The patient had been well until she was 2 months of age, when an episode of bronchiolitis occurred. After this episode, repeated respiratory illnesses characterized by wheezing and cyanosis developed, and she was hospitalized frequently. The patient was subsequently evaluated by a pediatric pulmonologist at this hospital. Examination revealed decreased breath sounds at the apex of the right lung, and chest radiography revealed findings suggestive of congenital lobar emphysema of the right upper lobe. A blood test for alpha 1-antitrypsin deficiency was negative. Transthoracic echocardiography revealed right ventricular dilatation and hypertrophy, mild pulmonary arterial hypertension, and a small patent ductus arteriosus. When the patient was 24 months of age, a right upper lobectomy, coil embolization for the patent ductus arteriosus, and a biopsy of the right middle lobe were performed. Dr. Mari Mino-Kenudson: Histopathological examination of lung specimens revealed lobar emphysema of the right upper and middle lobes that was characterized by the presence of fewer alveoli than the number typically seen in normal lung tissue and hyperinflation of the existing alveoli (Fig. 1A). The number of bronchioles in the peripheral emphysematous areas was disproportionately low relative to the number of pulmonary vessels, and the central bronchi had mucus plugs that may have obliterated the bronchial lumens (Fig. 1B). In the hilum, the central bronchi had mucus plugs that resulted in partial obstruction of the bronchial lumens, but the amount and contour of the bronchial cartilage were normal (Fig. 1C). No diagnostic findings were consistent with pulmonary hypertension. There are two possible causes of lobar emphysema in this case: obstruction (either

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A review of filamin A mutations and associated interstitial lung disease

Cited by 54 publications

References 20 publications

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene

Potential Molecular Pathways Related to Pulmonary Artery Aneurysm Development: Lessons to Learn from the Aorta

Case 28-2019: A 22-Year-Old Woman with Dyspnea and Chest Pain

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