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Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4.

ABSTRACT: We used exome sequencing to identify mutations in sideroflexin 4 (SFXN4) in two children with mitochondrial disease (the more severe case also presented with macrocytic anemia). SFXN4 is an uncharacterized mitochondrial protein that localizes to the mitochondrial inner membrane. sfxn4 knockdown in zebrafish recapitulated the mitochondrial respiratory defect observed in both individuals and the macrocytic anemia with megaloblastic features of the more severe case. In vitro and in vivo complementation studies with fibroblasts from the affected individuals and zebrafish demonstrated the requirement of SFXN4 for mitochondrial respiratory homeostasis and erythropoiesis. Our findings establish mutations in SFXN4 as a cause of mitochondriopathy and macrocytic anemia.

SUBMITTER: Hildick-Smith GJ

PROVIDER: S-EPMC3824126 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4.

Hildick-Smith Gordon J GJ Cooney Jeffrey D JD Garone Caterina C Kremer Laura S LS Haack Tobias B TB Thon Jonathan N JN Miyata Non N Lieber Daniel S DS Calvo Sarah E SE Akman H Orhan HO Yien Yvette Y YY Huston Nicholas C NC Branco Diana S DS Shah Dhvanit I DI Freedman Matthew L ML Koehler Carla M CM Italiano Joseph E JE Merkenschlager Andreas A Beblo Skadi S Strom Tim M TM Meitinger Thomas T Freisinger Peter P Donati M Alice MA Prokisch Holger H Mootha Vamsi K VK DiMauro Salvatore S Paw Barry H BH

American journal of human genetics 20131010 5

We used exome sequencing to identify mutations in sideroflexin 4 (SFXN4) in two children with mitochondrial disease (the more severe case also presented with macrocytic anemia). SFXN4 is an uncharacterized mitochondrial protein that localizes to the mitochondrial inner membrane. sfxn4 knockdown in zebrafish recapitulated the mitochondrial respiratory defect observed in both individuals and the macrocytic anemia with megaloblastic features of the more severe case. In vitro and in vivo complementa ...[more]

PMID: 24119684

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Project description:BackgroundUniatrial biventricular connection (UBC) is a rare cardiovascular anomaly characterized by absence of one atrioventricular connection and drainage of the other atrium via a solitary atrioventricular valve into both ventricles. The absent atrioventricular connection may affect either the left or right atrium. Because of the absence of one atrioventricular connection hearts with UBC have been classified among functionally univentricular hearts requiring palliative treatment according to the Fontan principle.Aims/objectiveWe report two further patients with UBC. In one of these patients careful echocardiographic examination of the atrioventricular junction in early infancy revealed the possibility of biventricular repair based on the favorable anatomy of the atrioventricular valve and balanced ventricles in the presence of an inlet ventricular septal defect (VSD).Case presentationsBoth patients presented in the neonatal period for evaluation of complex congenital heart disease. The anatomy of the atrioventricular valves in our patients was indistinguishable from atrioventricular septal defects exhibiting the morphology of a common valve with superior and inferior bridging leaflets. The common atrioventricular valve was connected exclusively to the right atrium draining into both ventricles while the left atrium drained into the right atrium via a secundum atrial septal defect. In one of our patients biventricular repair with good longterm-result was performed by reseptation of the atria, patch repair of the VSD and septation of the atrioventricular valve. The second patient underwent univentricular palliation according to the Fontan principle.Discussion/conclusionThe echocardiographic findings in our patients suggest that at least some patients with UBC represent a variant of atrioventricular septal defects associated with extreme ventriculoatrial malalignment resulting in fusion of the deviated primary atrial septum with the lateral aspect of the atrioventricular junction. This offers the option of septation of the common atrioventricular valve and biventricular repair in patients with adequate size of both ventricles. Exact echocardiographic analysis of the morphology of the atrioventricular valve is essential to distinguish these patients with a morphologically common atrioventricular valve in early infancy from other variants of absent atrioventricular connection and to select those who are suitable for biventricular repair.

Dataset Information

Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4.

Publications

Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4.

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