SUMF1 – Mucosulfatidosis (Multiple Sulfatase Deficiency)

Multiple sulfatase deficiency (mucosulfatidosis) is a rare autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in the SUMF1 gene encoding the formylglycine-generating enzyme (FGE), essential for post-translational activation of all sulfatases (PMID:12757706). A systematic review identified 143 unique MSD patients worldwide, delineating a broad clinical spectrum from severe neonatal forms to attenuated juvenile phenotypes (PMID:32621519).

Autosomal recessive inheritance is supported by multiple consanguineous families exhibiting segregation of biallelic SUMF1 variants with disease in at least 3 affected relatives (PMID:15146462). Penetrance is complete among homozygotes or compound heterozygotes, and carrier frequency is estimated ~1/700.

Pathogenic variants span 53 unique alleles, including 20 likely gene-disruptive mutations (nonsense, frameshift, splice-site) and diverse missense changes (PMID:32621519). Recurrent mutations include c.463T>C (p.Ser155Pro) and c.1045C>T (p.Arg349Trp) (PMID:16125993, PMID:17881260). We report c.463T>C (p.Ser155Pro) as a representative pathogenic missense variant.

Functional assays demonstrate that SUMF1 missense mutations severely impair FGE-mediated activation of multiple sulfatases, resulting in residual activities <1–25% of wild type (PMID:15146462, PMID:17657823). Structural elucidation of FGE and analysis of mutation sites provide a molecular basis for phenotype severity (PMID:15907468). Hypomorphic variants are properly localized yet subject to rapid ER-associated degradation, highlighting protein stability as a key mechanism (PMID:23321616).

Animal models engineered with patient-based SUMF1 variants, p.Ser153Pro and p.Ala277Val, recapitulate attenuated MSD phenotypes and extended lifespan, validating pathogenicity and offering platforms for therapeutic testing (PMID:36433920). Preclinical hematopoietic stem cell gene therapy restores sulfatase activities and improves neurocognitive outcomes in Sumf1−/− mice (PMID:39169621), underscoring translational potential.

Integration of extensive genetic, biochemical, and experimental data firmly establishes a definitive gene-disease relationship. Key Take-home: SUMF1 sequencing is critical for early diagnosis of mucosulfatidosis, informs prognosis, and guides emerging therapeutic strategies.

References

• Cell • 2003 • The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. PMID:12757706
• Human Mutation • 2004 • Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. PMID:15146462
• Cell • 2005 • Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme. PMID:15907468
• Journal of Inherited Metabolic Disease • 2020 • A systematic review and meta-analysis of published cases reveals the natural disease history in multiple sulfatase deficiency. PMID:32621519
• Journal of Inherited Metabolic Disease • 2023 • New mouse models with hypomorphic SUMF1 variants mimic attenuated forms of multiple sulfatase deficiency. PMID:36433920
• Molecular Therapy • 2024 • Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of multiple sulfatase deficiency. PMID:39169621

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