Kidney Week

Abstract: FR-PO313

Recurrent GATM Mutations Causing Autosomal Dominant Renal Fanconi Syndrome with Progressive Renal Failure

Session Information

• Fluid and Electrolytes: Clinical
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid and Electrolytes

• 902 Fluid and Electrolytes: Clinical

Authors

• Yan, Ming-Tso, National Defense Medical Center, Taipei, Taiwan

Ming-Tso Yan,

• Lin, Shih-Hua P., Tri-Service General Hospital, Neihu, Taiwan

Shih-Hua P. Lin,

Background

Inherited renal Fanconi syndrome without extrarenal manifestations, described as Fanconi renotubular syndrome (FRTS), have been reported to be caused by genetic defects in uncertain loci of chromosome 15 (type I), SLC34A1 (type II) and EHHADH (type III). In Type I characterized by autosomal dominant inheritance with late onset FRTS and progressive renal failure, its causative gene mutation is just reported to be caused by GATM encoding arginine-glycine aminotransferase (AGAT), an enzyme catalyzing rate-limiting step of creatine biosynthesis.

Methods

A Chinese family with typical autosomal dominant FRTS and progressive renal failure was enrolled. The affected father (age 60 and serum creatinine 6.1 mg/dl with eGFR 12 ml/min) and daughter (age 31, and serum creatinine 1.3 mg/dl, eGFR 50 ml/min) exhibited severe hypophosphatemia and hyperchloremic metabolic acidosis with distinctively osteomalacia as well as hypokalemia despite potassium, alkali, and vitamin D therapy. Sanger’s sequencing demonstrated no pathogenic mutations in SLC34A1 and EHHADH. Whole exome sequencing was performed in this family.

Results

Whole exome sequencing discovered a possible culprit missense mutation (p.Thr336Ile) in GATM, which mutation was identical to recent report, supporting the pathogenic role of GATM mutation in this unique type of FRTS. Localization of T336I mutation on 4^th β-sheet was suggested to transform 4^th β-sheet into a novel additional interaction surface, resulting in formation of linear AGAT multimer rather than physiological homodimer by interaction between 2^nd β-sheet. Because biallelic mutations in GATM causes cerebral creatine deficiency syndrome (CCDS) with neurological symptoms but not FRTS, the role of diminished total AGAT activity in pathogenesis of FRTS is unlikely.

Conclusion

Uniallelic GATM mutation clustering to a specific region may play a role in pathogenesis of autosomal dominant FRTS. Generation of GATM T336I knock-in mice is warranted to elucidate the mechanism of FRTS and assess the therapeutic role of creatine administration.