Probing the functional consequence and clinical relevance of <scp><i>CD320</i></scp> p.E88del, a variant in the transcobalamin receptor gene

Pangilinan, Faith; Watkins, David; Bernard, David; Chen, Yue; Dong, Ningzheng; Wu, Qingyu; Ozel-Abaan, Hatice; Kaur, Manjit; Casini, Michèle; Morrissey, Mark A.; Browne, Marilyn L.; Mills, James L.; Ryzin, Carol Van; Shchelochkov, Oleg A.; Sloan, Jennifer L.; Venditti, Charles P.; Sarafoglou, Kyriakie; Rosenblatt, David S.; Kay, Denise M.; Brody, Lawrence C.

doi:10.1002/ajmg.a.62627

Cited by 4 publications

(4 citation statements)

References 48 publications

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“…These include competing effects of cobalamin analogue formation in the body, 9 and possibly mutations or epigenetic alterations influencing the transcobalamin receptor. 80,81 An intriguing recent study has demonstrated that (auto)antibodies against the CD320 (transcobalamin) receptor may interfere with the proper uptake of cobalamin into the brain. 82 Long-term studies clearly indicate that treatment with pharmacological doses of B12 and the corresponding increase in serum B12 concentrations do not increase mortality risk.…”

Section: Monitoring Outcome and Follow-upmentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

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A Brief Overview of the Diagnosis and Treatment of Cobalamin (B12) Deficiency

Wolffenbuttel,

McCaddon,

Ahmadi

et al. 2024

Food Nutr Bull

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Background: An increasing number of adult individuals are at risk of vitamin B12 deficiency, either from reduced nutritional intake or impaired gastrointestinal B12 absorption. Objective: This study aims to review the current best practices for the diagnosis and treatment of individuals with vitamin B12 deficiency. Methods: A narrative literature review of the diagnosis and treatment of vitamin B12 deficiency. Results: Prevention and early treatment of B12 deficiency is essential to avoid irreversible neurological consequences. Diagnosis is often difficult due to diverse symptoms, marked differences in diagnostic assays' performance and the unreliability of second-line biomarkers, including holo-transcobalamin, methylmalonic acid and total homocysteine. Reduced dietary intake of B12 requires oral supplementation. In B12 malabsorption, oral supplementation is likely insufficient, and parenteral (i.e. intramuscular) supplementation is preferred. There is no consensus on the optimal long-term management of B12 deficiency with intramuscular therapy. According to the British National Formulary guidelines, many individuals with B12 deficiency due to malabsorption can be managed with 1000 µg intramuscular hydroxocobalamin once every two months after the initial loading. Long-term B12 supplementation is effective and safe, but responses to treatment may vary considerably. Clinical and patient experience strongly suggests that up to 50% of individuals require individualized injection regimens with more frequent administration, ranging from daily or twice weekly to every 2-4 weeks, to remain symptom-free and maintain a normal quality of life. ‘Titration’ of injection frequency based on measuring biomarkers such as serum B12 or MMA should not be practiced. There is currently no evidence to support that oral/sublingual supplementation can safely and effectively replace injections. Conclusions: This study highlights the interindividual differences in symptomatology and treatment of people with B12 deficiency. Treatment follows an individualized approach, based on the cause of the deficiency, and tailored to help someone to become and remain symptom-free.

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Section: Monitoring Outcome and Follow-upmentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

A Brief Overview of the Diagnosis and Treatment of Cobalamin (B12) Deficiency

Wolffenbuttel,

McCaddon,

Ahmadi

et al. 2024

Food Nutr Bull

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“…The three proteins act in succession, at specific points of the food-to-tissue delivery route. Inherited mutations of genes encoding IF (CBLIF 12,13 ), the IF receptor (CUBN, AMN 13,14 ) and TC (TCN2 15 ) are causative of disease, while the clinical relevance is uncertain for mutations of genes encoding the TC receptor (CD320 16 ) as well as HC (TCN1 17 ), which has no dedicated receptor.…”

Section: Structural Basis Of Cobalamin Absorptionmentioning

confidence: 99%

The complex machinery of human cobalamin metabolism

McCorvie

Ferreira

Yue

et al. 2023

J of Inher Metab Disea

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Vitamin B 12 (cobalamin, Cbl) is required as a cofactor by two human enzymes, 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) and methylmalonyl-CoA mutase (MMUT). Within the body, a vast array of transporters, enzymes and chaperones are required for the generation and delivery of these cofactor forms. How they perform these functions is dictated by the structure and interactions of the proteins involved, the molecular bases of which are only now being elucidated. In this review, we highlight recent insights into human Cbl metabolism and address open questions in the field by employing a protein structure and interactome based perspective. We discuss how three very similar proteins-haptocorrin, intrinsic factor and transcobalamin-exploit slight structural differences and unique ligand receptor interactions to effect selective Cbl absorption and internalisation. We describe recent advances in the understanding of how endocytosed Cbl is transported across the lysosomal membrane and the implications of the recently solved ABCD4 structure. We detail how MMACHC and MMADHC cooperate to modify and target cytosolic Cbl to the client enzymes MTR and MMUT using ingenious modifications to an ancient nitroreductase fold, and how MTR and MMUT link with their accessory enzymes to sustainably harness the supernucleophilic potential of Cbl. Finally, we provide an outlook on how future studies may combine structural and interactome based approaches and incorporate knowledge of post-translational modifications to bring further insights.

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“…The DSSDE motif is also present in other LDLR-containing cell surface receptors on the apical membrane in renal proximal tubules. CD320, for example, is a transcobalamin receptor for vitamin B12 uptake [55,56]. The N-terminal extracellular region of CD320 contains two LDLR domains, the second of which has a DSSDE motif (Figure 2).…”

Section: Regulation Of Sodium Homeostasis In Non-cardiac Tissuesmentioning

confidence: 99%

Corin: A Key Mediator in Sodium Homeostasis, Vascular Remodeling, and Heart Failure

Zhang

et al. 2022

Biology

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Atrial natriuretic peptide (ANP) is a crucial element of the cardiac endocrine function that promotes natriuresis, diuresis, and vasodilation, thereby protecting normal blood pressure and cardiac function. Corin is a type II transmembrane serine protease that is highly expressed in the heart, where it converts the ANP precursor to mature ANP. Corin deficiency prevents ANP activation and causes hypertension and heart disease. In addition to the heart, corin is expressed in other tissues, including those of the kidney, skin, and uterus, where corin-mediated ANP production and signaling act locally to promote sodium excretion and vascular remodeling. These results indicate that corin and ANP function in many tissues via endocrine and autocrine mechanisms. In heart failure patients, impaired natriuretic peptide processing is a common pathological mechanism that contributes to sodium and body fluid retention. In this review, we discuss most recent findings regarding the role of corin in non-cardiac tissues, including the kidney and skin, in regulating sodium homeostasis and body fluid excretion. Moreover, we describe the molecular mechanisms underlying corin and ANP function in supporting orderly cellular events in uterine spiral artery remodeling. Finally, we assess the potential of corin-based approaches to enhance natriuretic peptide production and activity as a treatment of heart failure.

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Probing the functional consequence and clinical relevance of CD320 p.E88del, a variant in the transcobalamin receptor gene

Cited by 4 publications

References 48 publications

A Brief Overview of the Diagnosis and Treatment of Cobalamin (B12) Deficiency

A Brief Overview of the Diagnosis and Treatment of Cobalamin (B12) Deficiency

The complex machinery of human cobalamin metabolism

Corin: A Key Mediator in Sodium Homeostasis, Vascular Remodeling, and Heart Failure

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