Mutation of the Mg2+ Transporter SLC41A1 Results in a Nephronophthisis-Like Phenotype

Hurd, T.W., Otto, E.A., Mishima, E., Gee, H.Y., Inoue, H., Inazu, M., Yamada, H., Halbritter, J., Seki, G., Konishi, M., Zhou, W., Yamane, T., Murakami, S., Caridi, G., Ghiggeri, G., Abe, T., and Hildebrandt, F.
Journal of the American Society of Nephrology : JASN   24(6): 967-977 (Journal)
Registered Authors
Zhou, Weibin
MeSH Terms
  • Animals
  • Cation Transport Proteins/genetics*
  • Cation Transport Proteins/metabolism*
  • Child
  • Child, Preschool
  • Dogs
  • Exons/genetics
  • Female
  • Genes, Recessive
  • HEK293 Cells
  • Heterozygote
  • Homozygote
  • Humans
  • Kidney/metabolism
  • Kidney/pathology
  • Kidney Diseases, Cystic/congenital*
  • Kidney Diseases, Cystic/genetics
  • Kidney Diseases, Cystic/metabolism
  • Kidney Diseases, Cystic/pathology
  • Madin Darby Canine Kidney Cells
  • Magnesium/metabolism*
  • Male
  • Membrane Proteins/genetics
  • Membrane Proteins/metabolism
  • Mutation, Missense
  • Pedigree
  • Zebrafish
  • Zebrafish Proteins
23661805 Full text @ J. Am. Soc. Nephrol.

Nephronophthisis (NPHP)-related ciliopathies are recessive, single-gene disorders that collectively make up the most common genetic cause of CKD in the first three decades of life. Mutations in 1 of the 15 known NPHP genes explain less than half of all cases with this phenotype, however, and the recently identified genetic causes are exceedingly rare. As a result, a strategy to identify single-gene causes of NPHP-related ciliopathies in single affected families is needed. Although whole-exome resequencing facilitates the identification of disease genes, the large number of detected genetic variants hampers its use. Here, we overcome this limitation by combining homozygosity mapping with whole-exome resequencing in a sibling pair with an NPHP-related ciliopathy. Whole-exome capture revealed a homozygous splice acceptor site mutation (c.698G>T) in the renal Mg2+ transporter SLC41A1. This mutation resulted in skipping of exon 6 of SLC41A1, resulting in an in-frame deletion of a transmembrane helix. Transfection of cells with wild-type or mutant SLC41A1 revealed that deletion of exon 6 completely blocks the Mg2+ transport function of SLC41A1. Furthermore, in normal human kidney tissue, endogenous SLC41A1 specifically localized to renal tubules situated at the corticomedullary boundary, consistent with the region of cystogenesis observed in NPHP and related ciliopathies. Last, morpholino-mediated knockdown of slc41a1 expression in zebrafish resulted in ventral body curvature, hydrocephalus, and cystic kidneys, similar to the effects of knocking down other NPHP genes. Taken together, these data suggest that defects in the maintenance of renal Mg2+ homeostasis may lead to tubular defects that result in a phenotype similar to NPHP.

Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes