Autosomal dominant ApoA4 mutations present as tubulointerstitial kidney disease with medullary amyloidosis
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
38096951
DOI
10.1016/j.kint.2023.11.021
PII: S0085-2538(23)00859-1
Knihovny.cz E-resources
- Keywords
- AApoA-IV, ApoA4, autosomal dominant tubulointerstitial kidney disease, medullary amyloidosis,
- MeSH
- Amyloidosis * MeSH
- Apolipoproteins A * MeSH
- Renal Insufficiency, Chronic * diagnosis genetics complications MeSH
- Nephritis, Interstitial * diagnosis genetics complications MeSH
- Middle Aged MeSH
- Humans MeSH
- Mutation MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- apolipoprotein A-IV MeSH Browser
- Apolipoproteins A * MeSH
Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m2, including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m2. Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies.
Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota USA
Department of Medicine University of Manitoba Winnipeg Manitoba Canada
Department of Pathology Faculty of Medicine Dalhousie University Halifax Nova Scotia Canada
Department of Quantitative Health Sciences Mayo Clinic Rochester Minnesota USA
Division of Nephrology and Hypertension Division of Hematology Mayo Clinic Rochester Minnesota USA
Institute of Microbiology of the Czech Academy of Sciences Vestec Czech Republic
Pathology Department Brigham and Women's Hospital Harvard Medical School Boston Massachusetts USA
Research Department of Pathology University College London London UK
Sano Genetics Limited London UK
Section on Nephrology Wake Forest University School of Medicine Winston Salem North Carolina USA
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