ApoA4 Mutations Cause Autosomal Dominant Tubulointerstitial Kidney Disease with Medullary Amyloidosis

Background: We describe for the first time mutations in the APOA4 gene as a cause of inherited kidney disease. Methods: Whole genome sequencing was performed in 5 members of a large family with autosomal dominant tubulointerstitial kidney disease(ADTKD), and we then screened other ADTKD families in our registry for mutations in the identified gene. Results: There was an ˜15 megabase shared genomic region on chromosome 11 (chr11: 110012896- 124998347) with only one relevant candidate variant chr11:116692578 G>C (hg19) encoding for a missense mutation in APOA4 (NM_000482.4): c.196C>G (p.L66V). Using Sanger sequencing and segregation analysis, we genotyped 19 individuals from the family. Of 12 genetically affected individuals (10 genotyped and two obligate heterozygotes), 10 had CKD, with two females being as yet clinically unaffected. Of nine genetically unaffected, the lowest eGFR was 59 ml/min/1.73m2 at age 69. Screening families from our ADTKD registry, we identified two other distantly related families with the same variant and two distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. All 31 clinically affected individuals suffered from CKD without proteinuria and a bland sediment and carried their familial pathogenic APOA4 mutation. The mean age of end-stage kidney disease was 72.7±10.2 for the p.L66V mutation and 58.2±1.1 for the p.D33N mutation (p=0.009). In an individual with the p.L66V mutation, pathologic examination of a nephrectomy specimen revealed marked medullary amyloid deposition, with mass-spectrometric analysis revealing the p.L66V ApoA4 protein as the predominant constituent. Four kidney biopsies containing only cortical tissue revealed no cortical amyloid deposition, while another biopsy containing cortex and medulla showed medullary amyloid deposits but no cortical amyloid deposits. In summary, ApoA4 mutations may lead to marked medullary amyloid deposition and ADTKD. Conclusions: For the first time, we identified mutations in the APOA4 gene as a cause of ADTKD. APOA4 mutations result in medullary ApoA4 deposition, which can be missed on routine kidney biopsies that only sample the renal cortex. Funding: Private Foundation Support

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.