A novel mutation in the SLC40A1 gene associated with reduced iron export in vitro

Abstract

Ferroportin disease is an inherited disorder of iron metabolism and is caused by mutations in the ferroportin gene (SLC40A1). We present a patient with hyperferritinemia, iron overload in the liver with reticuloendothelial distribution and also in the spleen, and under treatment with erythropheresis. A molecular study of the genes involved in iron metabolism (HFE, HJV, HAMP, TFR2, SLC40A1) was undertaken. In vitro functional studies of the novel mutation found in the SLC40A1 gene was performed. The patient was heterozygous for a novel mutation, c.386T>C (p.L129P) in the SLC40A1 gene; some of his relatives were also heterozygous for this mutation. In vitro functional studies of the L129P mutation on ferroportin showed it impairs its capacity to export iron from cells but does not alter its sensitivity to hepcidin. These findings and the iron overload phenotype of the patient suggest that the novel mutation c.386T>C (p.L129P) in the SLC40A1 gene has incomplete penetrance and causes the classical form of ferroportin disease.

A novel SLC40A1 p.Y333H mutation with gain of function of ferroportin: A recurrent cause of haemochromatosis in China

“…Mutations N144H/T/D, Y64N/H, L240E, C326Y/S/F, S338R, Y501C, D504N and H507R have been found in patients with FPN1 ‐associated haemochromatosis, but functional analysis is rarely reported. In vitro functional studies of the p.L129P mutation on ferroportin showed it impairs its capacity to export iron from cells but does not alter its sensitivity to hepcidin . Recently, a novel mutation p.R178Q was identified in 22 patients from six independent families in Europe, and in vitro studies showed that mutant reduced the ability of FPN1 to export iron without causing protein mislocalization .…”

A Five-Gene Signature Predicts Prognosis in Patients with Kidney Renal Clear Cell Carcinoma

“…Mutations in OTOF , which functionally triggers membrane fusion and exocytosis, may provide a link between calcium signaling and cancer [ 22 , 32 , 33 ]. SLC40A1 is a cell membrane protein that has been identified to mediate cellular iron efflux [ 23 , 34 ] and contribute to the invasive phenotype [ 35 ]. Mutations in ISPD may cause Walker-Warburg syndrome [ 36 , 37 ].…”

Developmental Physiology of Iron Absorption, Homeostasis, and Metabolism in the Healthy Term Infant

“…FPN is strongly regulated by iron status and is the only known ferrous iron exporter in mammals. FPN mutations in humans lead to iron-loading disorders (11). Ferrous iron is oxidized by hephaestin, a copper-containing membrane-bound ferroxidase that co-localizes with FPN in the basolateral membrane (12).…”