Novel CUBN Mutation in a Young Child With Megaloblastic Anemia

Abstract

Inherited disorders of cobalamin (Cbl, vitamin B12) metabolism are rare causes of megaloblastic anemia and neurologic abnormalities. More prevalent in certain ethnic groups, these disorders occur despite adequate Cbl intake and usually result from abnormal vitamin cell transport or processing. Cubilin (CUBN, intrinsic factor-cobalamin receptor) is the intestinal receptor for the endocytosis of intrinsic factor—vitamin B12. Its gene is localized to chromosome 10p13 and mutations involving CUBN have been described in patients with congenital megaloblastic anemia. In this report, we describe a novel CUBN pathogenic variant in a child with megaloblastic anemia.

Isolated benign persistent proteinuria with novel association of CUBN (cubilin) variants

“…Schematic of CUBN gene and exons, adapted from Domingo‐Gallego et al 2 Previously reported variants in exons 1–28 previously have been associated with IGS with megaloblastic anemia 2 . Variants in exons 29–67, the region encompassing c.5913_5916del (p.Thr1972Leufs*10) and c.5069C > T (p.Ala1690Val) which were reported here, have been associated with chronic benign proteinuria 2,8–12 …”

“…Few cases of benign isolated subnephrotic proteinuria in association with C‐terminal cubilin defects have been described in the literature. The spectrum of clinical presentations associated with CUBN pathogenic variants ranges from megaloblastic anemia type 1 (IGS) to isolated benign proteinuria 2,7–10 . The phenotype appears to be dependent on the site of the pathogenic variant within the CUBN gene and the loss of function of certain domains 2,10–12 .…”

“…10 CUBN variants noted in cases of IGS affect the N-terminal half of the encoded protein, which contains a domain responsible for vitamin B12 binding (Figure 1). 2,[10][11][12] In cases of renally isolated disease, CUBN variants affect amino acid sequence downstream of the B12 bindingdomain, suggesting that more C-terminal domains are crucial for urinary protein reabsorption, predominantly albumin (Figure 1). 2,5,[9][10][11][12] Existing literature is limited regarding the clinical manifestations and outcomes of isolated proteinuria associated with CUBN variants.…”

“…These proteins have limited expression in the small intestines and proximal tubules of the kidney. Defects in cubilin were previously only known to result in an autosomal recessive condition called Imerslund–Gräsbeck syndrome (IGS), which is characterized by intestinal vitamin B12 malabsorption, megaloblastic anemia, and, in half of cases, proteinuria 10 . CUBN variants noted in cases of IGS affect the N‐terminal half of the encoded protein, which contains a domain responsible for vitamin B12 binding (Figure 1).…”

“…2,[10][11][12] In cases of renally isolated disease, CUBN variants affect amino acid sequence downstream of the B12 bindingdomain, suggesting that more C-terminal domains are crucial for urinary protein reabsorption, predominantly albumin (Figure 1). 2,5,[9][10][11][12] Existing literature is limited regarding the clinical manifestations and outcomes of isolated proteinuria associated with CUBN variants. The first known cases were two children born to consanguineous parents with homozygous deleterious frameshift variants in CUBN.…”