CUBN – Imerslund-Grasbeck Syndrome

Imerslund-Grasbeck syndrome (IGS) is a rare autosomal recessive disorder characterized by selective intestinal malabsorption of vitamin B₁₂ leading to megaloblastic anemia and asymptomatic proteinuria. Bi-allelic mutations in CUBN, encoding the cubilin subunit of the intrinsic factor–cobalamin receptor, underlie one major molecular form of IGS and account for cases clustered by founder effects and consanguinity in multiple populations.

Genetic studies have identified CUBN mutations in 42 sibships with juvenile megaloblastic anemia ([PMID:15024727]) and in a family of four siblings homozygous for a frameshift variant ([PMID:31497480]). All affected individuals exhibit autosomal recessive inheritance of loss-of-function alleles, including nonsense, frameshift, and splice-site variants. Representative pathogenic variant c.2614_2615del (p.Asp872LeufsTer3) leads to truncated cubilin and manifests with classical IGS features in homozygous patients.

The variant spectrum in CUBN is dominated by >30 alleles predicted to abolish protein function, with founder mutations described in Finnish and Mediterranean cohorts. Multiplex families demonstrate allelic heterogeneity and confirm recessive transmission. Single exon and deep-intronic changes also contribute to the phenotype, supporting genetic testing across the gene.

Functional assays corroborate clinical findings: the recurrent p.Pro1297Leu substitution reduces intrinsic factor–vitamin B₁₂ binding affinity, increasing K_d several-fold ([PMID:10887099]). In patients, intramuscular hydroxycobalamin supplementation corrects hematologic and growth abnormalities and ameliorates lethargy and mucosal ulcerations, demonstrating treatment efficacy ([PMID:31497480]).

Clinically, affected individuals present in infancy or early childhood with megaloblastic anemia, proteinuria, lethargy, oral ulcers, and failure to thrive. Proximal tubular proteinuric changes occur without progressive glomerular impairment. Early diagnosis and lifelong B₁₂ replacement prevent hematologic and developmental complications.

Collectively, robust genetic and experimental evidence supports a Strong association between CUBN and Imerslund-Grasbeck syndrome. Molecular screening for CUBN variants enables definitive diagnosis, informs prognosis, and guides prompt hydroxycobalamin therapy. Key Take-home: biallelic CUBN mutations cause IGS with reversible hematologic and growth defects when treated early.

References

• Human Mutation • 2004 • Genetically heterogeneous selective intestinal malabsorption of vitamin B12: founder effects, consanguinity, and high clinical awareness explain aggregations in Scandinavia and the Middle East PMID:15024727
• JIMD reports • 2019 • Profound vitamin D deficiency in four siblings with Imerslund-Grasbeck syndrome with homozygous CUBN mutation PMID:31497480
• Blood • 2000 • Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin PMID:10887099

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