Novel compound heterozygous mutations of CLDN16 in a patient with familial hypomagnesemia with hypercalciuria and nephrocalcinosis
García-Castaño, Alejandro (Instituto de Investigación Sanitaria Biocruces Bizkaia)
Perdomo-Ramirez, Ana (Hospital Universitario Nuestra Señora de Candelaria (Santa Cruz de Tenerife))
Vall-Palomar, Mònica (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Ramos-Trujillo, Elena (Hospital Universitario Nuestra Señora de Candelaria (Santa Cruz de Tenerife))
Madariaga, Leire (Hospital Universitario de Cruces (Barakaldo, País Basc))
Ariceta Iraola, Gema (Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i Medicina Preventiva i Salut Pública)
Claverie-Martin, Felix (Hospital Universitario Nuestra Señora de Candelaria (Santa Cruz de Tenerife))

Data:	2020
Resum:	Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubulopathy characterized by excessive urinary wasting of magnesium and calcium, bilateral nephrocalcinosis, and progressive chronic renal failure in childhood or adolescence. FHHNC is caused by mutations in CLDN16 and CLDN19, which encode the tight-junction proteins claudin-16 and claudin-19, respectively. Most of these mutations are missense mutations and large deletions are rare. We examined the clinical and biochemical features of a Spanish boy with early onset of FHHNC symptoms. Exons and flanking intronic segments of CLDN16 and CLDN19 were analyzed by direct sequencing. We developed a new assay based on Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF) to investigate large CLDN16 deletions. Genetic analysis revealed two novel compound heterozygous mutations of CLDN16, comprising a missense mutation, c. 277G>A; p. (Ala93Thr), in one allele, and a gross deletion that lacked exons 4 and 5,c. (840+25_?)del, in the other allele. The patient inherited these variants from his mother and father, respectively. Using direct sequencing and our QMPSF assay, we identified the genetic cause of FHHNC in our patient. This QMPSF assay should facilitate the genetic diagnosis of FHHNC. Our study provided additional data on the genotypic spectrum of the CLDN16 gene. We report the clinical and genetic findings of a child diagnosed with FHHNC, a rare autosomal recessive disease characterized by excessive renal magnesium and calcium wasting, bilateral nephrocalcinosis, and progressive chronic renal failure. Two novel compound heterozygous mutations of CLDN16, c. 277G>A, p. (A93T) and a gross deletion involving exons 4 and 5, inherited from the patient's parents, were identified. We developed a new assay based on Quantitative Multiplex PCR of Short Fluorescent Fragments, which should facilitate the genetic diagnosis of FHHNC.
Ajuts:	Instituto de Salud Carlos III PI17-00153
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Claudin-16 ; CLDN16 ; Deletion ; Hypomagnesemia ; Novel mutations ; QMPSF
Publicat a:	Molecular genetics & genomic medicine, Vol. 8 (september 2020) , ISSN 2324-9269

DOI: 10.1002/mgg3.1475
PMID: 32869508

10 p, 1.1 MB

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