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Profound vitamin D deficiency in four siblings with Imerslund-Grasbeck syndrome with homozygous CUBN mutation.

ABSTRACT: Imerslund-Grasbeck syndrome (IGS, OMIM 261100) is a rare autosomal recessive disease characterized by vitamin B12 malabsorption resulting in megaloblastic anemia and asymptomatic proteinuria. IGS is caused by bi-allelic mutations in either CUBN or AMN that respectively encode the cubilin and amnionless subunits of the cobalamin-intrinsic factor receptor. We report four siblings (three boys, one girl) of non-consanguineous parents of Jewish background, aged 10 months to 12?years, with homozygous CUBN frameshift c.2614_2615deIGA p.(Asp872LeufisTer3) mutation and typical features of IGS. The two older brothers presented in early infancy with lethargy, mouth ulcerations, eosinophilic enterocolitis, megaloblastic anemia and failure to thrive. Investigations revealed low serum cobalamin levels. Intramuscular hydroxycobalamin supplementation resulted in dramatic resolution of all symptoms including lethargy. A positive impact on their growth curve was seen. Prospective early treatment in the younger siblings prevented these manifestations. Proteinuria with proximal tubulopathy was seen in all patients, plasma protein level and renal function were normal. All children had pronounced vitamin D deficiency and required high doses of oral supplementation. Vitamin B12 treatment could be individually adjusted; requirement decreased with age. Tubulopathy showed improvement over time. Low vitamin D could be explained by cubilin being involved in reabsorption of vitamin carriers.

SUBMITTER: Ciancio JIR

PROVIDER: S-EPMC6718117 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Profound vitamin D deficiency in four siblings with Imerslund-Grasbeck syndrome with homozygous CUBN mutation.

Ciancio Jose I R JIR Furman Mark M Banka Siddharth S Grunewald Stephanie S

JIMD reports 20190726 1

Imerslund-Grasbeck syndrome (IGS, OMIM 261100) is a rare autosomal recessive disease characterized by vitamin B12 malabsorption resulting in megaloblastic anemia and asymptomatic proteinuria. IGS is caused by bi-allelic mutations in either CUBN or AMN that respectively encode the cubilin and amnionless subunits of the cobalamin-intrinsic factor receptor. We report four siblings (three boys, one girl) of non-consanguineous parents of Jewish background, aged 10 months to 12 years, with homozygous ...[more]

PMID: 31497480

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Project description:BACKGROUND: Imerslund-Gräsbeck Syndrome (IGS) is a rare genetic disorder characterised by juvenile megaloblastic anaemia. IGS is caused by mutations in either of the genes encoding the intestinal intrinsic factor-vitamin B12 receptor complex, cubam. The cubam receptor proteins cubilin and amnionless are both expressed in the small intestine as well as the proximal tubules of the kidney and exhibit an interdependent relationship for post-translational processing and trafficking. In the proximal tubules cubilin is involved in the reabsorption of several filtered plasma proteins including vitamin carriers and lipoproteins. Consistent with this, low-molecular-weight proteinuria has been observed in most patients with IGS. The aim of this study was to characterise novel disease-causing mutations and correlate novel and previously reported mutations with the presence of low-molecular-weight proteinuria. METHODS: Genetic screening was performed by direct sequencing of the CUBN and AMN genes and novel identified mutations were characterised by in silico and/or in vitro investigations. Urinary protein excretion was analysed by immunoblotting and high-resolution gel electrophoresis of collected urines from patients and healthy controls to determine renal phenotype. RESULTS: Genetic characterisation of nine IGS patients identified two novel AMN frameshift mutations alongside a frequently reported AMN splice site mutation and two CUBN missense mutations; one novel and one previously reported in Finnish patients. The novel AMN mutations were predicted to result in functionally null AMN alleles with no cell-surface expression of cubilin. Also, the novel CUBN missense mutation was predicted to affect structural integrity of the IF-B12 binding site of cubilin and hereby most likely cubilin cell-surface expression. Analysis of urinary protein excretion in the patients and 20 healthy controls revealed increased urinary excretion of cubilin ligands including apolipoprotein A-I, transferrin, vitamin D-binding protein, and albumin. This was, however, only observed in patients where plasma membrane expression of cubilin was predicted to be perturbed. CONCLUSIONS: In the present study, mutational characterisation of nine IGS patients coupled with analyses of urinary protein excretion provide additional evidence for a correlation between mutation type and presence of the characteristic low-molecular-weight proteinuria.

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Profound vitamin D deficiency in four siblings with Imerslund-Grasbeck syndrome with homozygous CUBN mutation.

Publications

Profound vitamin D deficiency in four siblings with Imerslund-Grasbeck syndrome with homozygous CUBN mutation.

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