Abnormal mitoferrin-1 expression in patients with erythropoietic protoporphyria

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Erythropoietic protoporphyria (EPP) is often linked to deficient ferrochelatase (FECH) activity due to FECH gene mutations.
• This study investigated EPP patients with normal FECH DNA to explore alternative causes.

Purpose of the Study:

• To investigate the role of mitoferrin-1 (MFRN1), an iron transporter crucial for FECH function, in patients with EPP phenotype but without identified FECH DNA abnormalities.
• To determine if MFRN1 dysfunction contributes to EPP.

Main Methods:

• Analysis of ALAS2 and FECH genes in seven EPP patients.
• Examination of MFRN1 messenger RNA (mRNA) transcripts in patient blood and liver samples.
• Functional studies using zebrafish and yeast models, and patient-derived lymphoblasts.

Main Results:

• Four patients had ALAS2 gain-of-function mutations; one had a FECH deletion.
• All patients exhibited abnormal MFRN1 transcripts with an intron 2 insertion and a stop codon.
• Abnormal MFRN1 complementary DNA (cDNA) demonstrated loss-of-function, while normal MFRN1 cDNA rescued MFRN1-deficient models.
• Patient lymphoblasts showed increased abnormal MFRN1 transcript, decreased normal MFRN1 mRNA, and reduced FECH activity, correlating with FECH activity (r=0.75).

Conclusions:

• Abnormal MFRN1 expression is a potential contributor to the EPP phenotype in some individuals.
• This dysfunction likely occurs through a reduction in FECH activity, independent of direct FECH DNA defects.