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Identification of a Novel Homozygous Missense Mutation in the CLDN16 Gene to Decipher the Ambiguous Clinical Presentation Associated with Autosomal Dominant Hypocalcaemia and Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis in an Indian Family

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Abstract

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHNNC) is a rare autosomal recessive renal tubulopathy disorder characterized by excessive urinary loss of calcium and magnesium, polyuria, polydipsia, bilateral nephrocalcinosis, progressive chronic kidney disease, and renal failure. Also, sometimes amelogenesis imperfecta and severe ocular abnormalities are involved. The CLDN-16 and CLDN-19 genes encode the tight junction proteins claudin-16 and claudin-19, respectively, in the thick ascending loop of Henle in the kidney, epithelial cells of the retina, dental enamel, etc. Loss of function of the CLDN-16 and/or CLDN-19 genes leads to FHHNC. We present a case of FHHNC type 1, which was first confused with autosomal dominant hypocalcaemia (ADH) due to the presence of a very low serum parathyroid hormone (PTH) concentration and other similar clinical features before the genetic investigations. After the exome sequencing, FHHNC type 1 was confirmed by uncovering a novel homozygous missense mutation in the CLDN-16 gene (Exon 2, c.374 T > C) which causes, altered protein structure with F55S. Associated clinical, biochemical, and imaging findings also corroborate final diagnosis. Our findings expand the spectrum of the CLDN-16 mutation, which will further help in the genetic diagnosis and management of FHNNC.

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Data Availability

The genetic analysis data file is available on request.

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Acknowledgements

The authors acknowledge the necessary support of the Director, NIBMG, authorities of Burdwan Medical College and Hospital, Burdwan, and authorities of Burdwan University, and are thankful to the parents of the patient for agreeing to the present study. RT expresses thanks and acknowledgment to UGC for the NET fellowship.

Funding

The present study was partially supported by the UGC NET fellowship (RT) and intramural grant support of AB from NIBMG.

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  1. Rupesh Thapa and Amaresh Roy have contributed equally to this work.

Authors and Affiliations

  1. The University of Burdwan, Burdwan, WB, India

    Rupesh Thapa & Anupam Basu

  2. Department of Paediatric Medicine, Burdwan Medical College, and Hospital, Burdwan, WB, India

    Amaresh Roy & Kaustav Nayek

  3. National Institute of Biomedical Genomics, Kalyani, WB, India

    Rupesh Thapa & Anupam Basu

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  1. Rupesh Thapa
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Contributions

RT did the genetic work and wrote the manuscript; AR did the clinical workup; and KN supervised the clinical workup. AB supervises the genetic work and checks the final manuscript.

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Correspondence to Kaustav Nayek or Anupam Basu.

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Rupesh Thapa, Amaresh Roy, Kaustav Nayek and Anupam Basu deny any kind of conflict of interest in the present study.

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Blood samples was sent to the laboratory for the genetic study as per approval of ethics committee and informed consent was taken from the parents.

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Thapa, R., Roy, A., Nayek, K. et al. Identification of a Novel Homozygous Missense Mutation in the CLDN16 Gene to Decipher the Ambiguous Clinical Presentation Associated with Autosomal Dominant Hypocalcaemia and Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis in an Indian Family. Calcif Tissue Int 114, 110–118 (2024). https://doi.org/10.1007/s00223-023-01142-8

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