SUGP2 – Hereditary Hemochromatosis

This summary reviews evidence linking SUGP2 (HGNC:18641) with hereditary hemochromatosis (MONDO_0006507). Multiple independent studies in Chinese cohorts identified non‐HFE variants in primary iron overload patients. In particular, a recurrent SUGP2 variant, c.1916G>A (p.Arg639Gln), has been reported in several probands and appears in combination with other mutations in genes of the BMP/SMAD pathway, strengthening the genetic association (PMID:30166352).

Genetic evidence stems from two major multi‐patient studies. The first study evaluating non‐HFE mutations in haemochromatosis identified the SUGP2 p.Arg639Gln variant in all three probands with HJV signal peptide mutations, while a second study in 32 primary iron overload patients detected likely pathogenic SUGP2 variants in 8 cases, with 19 patients carrying heterozygous or combined mutations (PMID:34583728). Pedigree analyses across these families support segregation of the SUGP2 variant with the iron overload phenotype.

The inheritance pattern for this association is consistent with an autosomal recessive mode. Affected individuals generally harbor compound heterozygous or combined heterozygous variants, although the involvement of other interacting genes suggests a complex allelic architecture. Segregation analyses in familial cases reveal that additional affected relatives also carry segregating variants, underpinning the pathogenic role of SUGP2 in the context of non‐HFE haemochromatosis.

Functional studies further bolster the role of SUGP2 in iron regulation. In vitro assays using siRNA knockdown of SUGP2 demonstrated downregulation of the BMP/SMAD pathway, while site‐directed mutagenesis experiments recapitulated the loss of membrane localization and decreased expression of key iron regulatory proteins. Moreover, CRISPR-Cas9 knock-in models of the SUGP2 p.Arg639Gln variant exhibited increased liver iron accumulation and decreased hepcidin levels, establishing a mechanistic link between the SUGP2 variant and disease phenotype (PMID:38800953).

Collectively, the genetic and functional evidence converge to support a strong association between SUGP2 and hereditary hemochromatosis. The recurrent identification of c.1916G>A (p.Arg639Gln) across multi-patient cohorts, combined with robust functional data, provides clinical utility for diagnostic decision‑making and may inform future therapeutic interventions.

Key take‑home sentence: The integration of multi-patient genetic data and corroborative functional studies confirms that SUGP2, particularly via its recurrent c.1916G>A (p.Arg639Gln) variant, is a valuable diagnostic marker for non-HFE hereditary hemochromatosis.

References

• Journal of Medical Genetics • 2018 • Non-HFE mutations in haemochromatosis in China: combination of heterozygous mutations involving HJV signal peptide variants PMID:30166352
• Orphanet Journal of Rare Diseases • 2021 • Correlation of genotype and phenotype in 32 patients with hereditary hemochromatosis in China PMID:34583728
• American Journal of Hematology • 2024 • SUGP2 p.(Arg639Gln) variant is involved in the pathogenesis of hemochromatosis via the CIRBP/BMPER signaling pathway PMID:38800953

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