Type 4B hereditary hemochromatosis associated with a novel mutation in the SLC40A1 gene

Abstract

Rationale:Hereditary hemochromatosis can be divided into HFE- and non-HFE-related based on genetic mutations in different genes. HFE-related hemochromatosis is the most common inherited genetic disease in European populations but rare in Asia-pacific region. Recently, non-HFE-related hemochromatosis has been reported in patients from the Asian countries.Patient concerns:We report the case of a 48-year-old Chinese Han woman who presented with abnormal liver function, diabetes mellitus, hyperferritinemia, and high transferrin saturation, with severe iron overload in parenchymal cells, Kupffer cells, and periportal fibrosis on liver biopsy. No secondary factor for iron overload was identified.Diagnoses:Sanger sequencing was conducted for the screening of mutation in the hereditary hemochromatosis related genes. The functional effect of a splicing mutation, SLC40A1 IVS 3+10 del gtt, was assessed by reverse-polymerase chain reaction analysis for SLC40A1 mRNA level, and by immunohistochemistry analysis of liver biopsy for ferroportin expression and cellular localization.Outcomes:A novel splicing mutation IVS 3+10 del gtt was identified in the SLC40A1 gene. Functional analysis showed that IVS 3+10 del gtt in the SLC40A1 gene lead to a substantial reduction in the basal levels of SLC40A1 mRNA and increased membrane localization of ferroportin. Finally, the patient was diagnosed as ferroportin disease (type 4B hemochromatosis).Lessons:The present study is the first report to identify a classical splicing mutation in the SLC40A1 gene in type 4B hemochromatosis, and provide further evidence of the prevalence of type 4 hereditary hemochromatosis in Asian countries.

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

“…Although the majority of these are reported as pathogenic, there may be some doubt in cases that lacked phenotypic, segregation or functional data . SLC40A1 mutations have been reported in Chinese haemochromatosis patients, including missense mutations W158C and S209L, small deletions mutation V162del and splicing variants IVS 3+10 del gtt and IVS1‐8C/G …”

Hyperferritinaemia and iron overload in Asian patients: lessons from an Australian tertiary centre experience

“…However, novel non- HFE gene mutations such as haemojuvelin (HJV/HFE2) and ferroportin (SLC40A1) have been identified in Asian patients with iron overload. [14][15][16][17] The lack of information in Asian haemochromatosis is likely to be due to its low prevalence and mild phenotype. However, the prevalence of hyperferritinaemia is higher in Asians than Caucasians and true cases of iron overload in Asian patients may be even rarer as secondary causes, such as liver disease, metabolic syndrome and alcoholism account for most cases.…”

“…Therefore, HFE testing is not indicated in Asian patients with hyperferritinaemia. However, novel non‐HFE gene mutations such as haemojuvelin (HJV/HFE2) and ferroportin (SLC40A1) have been identified in Asian patients with iron overload 14–17 …”

Membrane Transport Proteins in Osteoclasts: The Ins and Outs

“…This is exemplified in patients with iron overload conditions such as hemochromatosis, thalassemia and sickle cell disease, which frequently suffer osteoporosis and associated fragility fractures (Guggenbuhl et al, 2005;Fung et al, 2008). Hemochromatosis, in particular, has been reported to arise from mutations in SLC40A1 (Zhang et al, 2017;Ka et al, 2018;Yin et al, 2019). SLC40A1, also known as Ferroportin 1 and SLC11A3, is a 571-amino acid transporter localized to cell membranes where it functions to facilitate iron export (Hentze et al, 2004).…”