ClinVar

In 6 members of 3 unrelated French families (families 2, 3, and 4) diagnosed with iron overload (IO; 620121) as adults, Daher et al. (2016) identified a heterozygous c.287T-C transition (c.287T-C, NM_001718) in exon 1 of the BMP6 gene, resulting in a leu96-to-pro (L96P) substitution at a highly conserved residue in the propeptide domain. The mutation, which was found by direct sequencing, segregated with the disorder in the families, although there was evidence of incomplete penetrance. Haplotype analysis did not indicate a founder effect. The L96P variant was present at a low frequency in the Exome Variant Server database (17 of 7,969 alleles). Two additional individuals with the disorder associated with an L96P mutation were subsequently identified in replication cohorts, including 1 who also carried a heterozygous mutation in the HFE gene (H63D; 613609.0002). In vitro studies in OK cells expressing the mutation showed that the mutant protein accumulated primarily in cytosolic aggregates, resulting in decreased secretion. The mutation impaired BMP6-induced activation of the downstream SMAD signaling pathway, with decreased induction of hepcidin (HAMP; 606464) expression. The mutant protein was able to form heterodimers with wildtype BMP6 and acted in a dominant-negative manner.

In a 54-year-old Italian man (patient 01) with IO, Piubelli et al. (2017) identified a heterozygous L96P mutation in the BMP6 gene. The patient also carried a heterozygous mutation in the HFE gene (H63D; 613609.0002). The mutation was found by next-generation sequencing using a panel and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. Among 111 Italian controls, 2 were found to carry the L96P variant, yielding a frequency of 0.009 in the population. The patient had a severe disease with metabolic syndrome and a history of alcohol consumption, both of which were aggravating factors; he died of cirrhosis shortly after presentation.