Abstract: TH-PO585

Recessive Mutations of MAP7D3 Cause a Renal Ciliopathy

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases

Authors

  • Jobst-Schwan, Tilman, Boston Children's Hospital, Boston, Massachusetts, United States
  • Goncalves, Joao, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada
  • Lahav, Einat, Sheba Medical Center, Safra Children's Hospital, Division of Pediatric Nephrology, Pediatric Stem Cell Research Institute, Ramat Gan, Israel
  • Stein, Deborah R., Boston Children's Hospital, Boston, Massachusetts, United States
  • Dekel, Benjamin, Sheba Medical Center, Safra Children's Hospital, Division of Pediatric Nephrology, Pediatric Stem Cell Research Institute, Ramat Gan, Israel
  • Pelletier, Laurence, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background

Renal ciliopathies are characterized by dysfunction of the primary cilium and centrosomes. Mutations in one of 95 genes have been discovered to cause these single gene-disorders in ~65% of patients with renal ciliopathies.

Methods

To identify novel ciliopathy genes, we analyzed whole exome sequencing (WES) data in individuals with ciliopathies, who had no mutations in any known ciliopathy genes. We examined the subcellular localization of MAP7D3 using confocal immunofluorescence (IF) analysis in and performed co-immunoprecipitation (co-IP) to test the interactions with other known ciliopathy genes.

Results

The male index patient from a non-consanguineous family presented with polyuria, enuresis, tubular proteinuria, impaired kidney function (GFR 30ml/min) and acidosis. Renal ultrasound (US) showed small, echogenic kidneys. By WES trio analysis, we identified the hemizygous truncating mutation c.1284_1285insC (p.Ser429Glnfs) in the X-chromosomal MAP7D3 gene in this patient.
In a second unrelated non-consanguineous family, the male patient presented with severe hyperkalemia, small echogenic kidneys upon US and end stage renal disease. Renal biopsy of this patient showed nephronophthisis-like features with additional glomerulosclerosis. By WES, we identified the hemizygous missense mutation c.65G>C, p.Arg22Pro in MAP7D3 introducing a proline residue in a coiled-coil domain that is known to interact with microtubules.
By IF, we show that wild type Flag-BirA-MAP7D3 localizes to the mitotic spindle. By co-IP, we show that wild type MAP7D3 interacts with CEP120, mutated in the ciliopathy Jeune asphyxiating thoracic dystrophy, and with SPICE1 as well as CP110, which are all centrosomal proteins.

Conclusion

We here identify mutations of MAP7D3 as a novel monogenic cause of a renal ciliopathy in humans and demonstrate that the protein interacts with other ciliopathy associated or centrosomal proteins. Further studies will elucidate allele specific expression and pathogenic pathways involved.

Funding

  • NIDDK Support