Rare autosomal dominant hereditary hemochromatosis associated with SLC40A1 gene: ferroportin disease or type 4 hereditary hemochromatosis?

Simão, Rita; Fleming, Rita; Mendonça, Joana; Machado, Miguel P.; Vieira, Luís; Tavares, Wilson; Lavinha, João; Faustino, Paula

Publication

Rare autosomal dominant hereditary hemochromatosis associated with SLC40A1 gene: ferroportin disease or type 4 hereditary hemochromatosis?

2019-11Conference object

dc.contributor.author	Simão, Rita
dc.contributor.author	Fleming, Rita
dc.contributor.author	Mendonça, Joana
dc.contributor.author	Machado, Miguel P.
dc.contributor.author	Vieira, Luís
dc.contributor.author	Tavares, Wilson
dc.contributor.author	Lavinha, João
dc.contributor.author	Faustino, Paula
dc.date.accessioned	2020-05-21T10:36:06Z
dc.date.available	2020-05-21T10:36:06Z
dc.date.issued	2019-11
dc.description.abstract	Ferroportin (FPN1), encoded by the SLC40A1 gene, is the unique cellular iron exporter identified in mammals. FPN1 transfers iron from the intestine and macrophages into the bloodstream. This function is negatively regulated by hepcidin. Mutations in SLC40A1 may affect FPN1 function, originating distinct autosomal dominant diseases: (i) the Ferroportin Disease (FD), due to loss-of-function mutations, is characterized by decreased iron export from enterocytes and severely affected iron transfer in macrophages, giving rise to a marked iron accumulation in spleen and liver; and (ii) the Type 4 Hereditary Hemochromatosis (HH), resulting from gain-of-function mutations conferring resistance to hepcidin-mediated FPN1 degradation and consequently high cellular iron export. In this study, 335 individuals suspected of having non-classic HH were enrolled. Six genes related with iron metabolism were analysed by SSCP, dHPLC or NGS. The latter used TruSeq or Nextera XT libraries and a MiSeq platform (Illumina). Genetic variants found were validated by Sanger sequencing. Predictive consequences at protein level were evaluated using Polyphen-2 and SIFT softwares. From all patients analysed, three SLC40A1 pathogenic variants were detected in heterozygosity in three women: two missense, c.238G>A, p.Gly80Ser and c.610G>A, p.Gly204Ser; and one deletion, c.485_487delTTG; p.Val162del. These variants had been reported in public databases, but they were not known to be present in the Portuguese population. The p.Gly80Ser and the p.Val162del are FPN1 loss-of-function mutations and were found associated with hyperferritinemia and low transferrin saturation (FD). In contrast, the p.Gly204Ser induced a gain of FPN1 function with a full iron export capacity giving the patient a type 4-HH phenotype, which includes iron overload, hyperferritinemia and high transferrin saturation. Detailed clinical evaluation of the suspected patients are useful to unravel the effect of different mutations in FPN1 function, expression and regulation.	pt_PT
dc.description.sponsorship	This work was partially supported by INSA_2013DGH910 and GenomePT (POCI-01-0145-FEDER-022184).	pt_PT
dc.description.version	info:eu-repo/semantics/publishedVersion	pt_PT
dc.identifier.uri	http://hdl.handle.net/10400.18/6727
dc.language.iso	eng	pt_PT
dc.peerreviewed	yes	pt_PT
dc.rights.uri	http://creativecommons.org/licenses/by-nc/4.0/	pt_PT
dc.subject	Ferroportin	pt_PT
dc.subject	SLC40A1	pt_PT
dc.subject	Doenças Genéticas	pt_PT
dc.subject	Doenças Raras	pt_PT
dc.subject	Metabolismo do Ferro	pt_PT
dc.subject	Doença da Ferroportina	pt_PT
dc.title	Rare autosomal dominant hereditary hemochromatosis associated with SLC40A1 gene: ferroportin disease or type 4 hereditary hemochromatosis?	pt_PT
dc.type	conference object
dspace.entity.type	Publication
oaire.citation.conferencePlace	Coimbra, Portugal	pt_PT
oaire.citation.title	23nd Annual Meeting of the Portuguese Society of Human Genetics, 14-16 Novembro 2019	pt_PT
person.familyName	Faustino
person.givenName	Paula
person.identifier.ciencia-id	F01A-353A-433E
person.identifier.orcid	0000-0002-6269-4867
person.identifier.rid	M-3519-2014
person.identifier.scopus-author-id	8158641100
rcaap.rights	openAccess	pt_PT
rcaap.type	conferenceObject	pt_PT
relation.isAuthorOfPublication	94303e78-8b7d-4e24-811d-3af3b1a4e330
relation.isAuthorOfPublication.latestForDiscovery	94303e78-8b7d-4e24-811d-3af3b1a4e330