TY - JOUR
T1 - Reduced guanidinoacetate in plasma of patients with autosomal dominant Fanconi syndrome due to heterozygous P341L GATM variant and study of organoids towards treatment
AU - Portales-Castillo, Ignacio
AU - Singal, Rhea
AU - Ambrose, Anastasia
AU - Song, Jong Hee
AU - Son, Minsoo
AU - Goo, Young Ah
AU - Zhou, Wen
AU - Traum, Avram Z.
AU - Coler-Reilly, Ariella
AU - Humphreys, Benjamin D.
AU - Civitelli, Roberto
AU - Jüppner, Harald
AU - Lundquist, Andrew L.
AU - Seres, Peter
AU - Allegretti, Andrew S.
AU - Mercimek-Andrews, Saadet
N1 - Publisher Copyright:
© 2024 The Author(s). JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.
PY - 2024/9
Y1 - 2024/9
N2 - Autosomal dominant Fanconi syndrome due to a GATM variant (GATM-FS), causes accumulation of misfolded arginine-glycine amidinotransferase (AGAT) in proximal renal tubules leading to cellular injury. GATM-FS presents during childhood and progresses to end-stage kidney disease (ESKD) in adults. We study creatine metabolism in two individuals of unrelated families with a known GATM variant and the effect of creatine supplementation in kidney organoids. Plasma and urine metabolites were measured by mass spectrometry. Brain creatine was assessed by magnetic resonance spectroscopy (MRS). Guanidinoacetate (GAA) synthesis by the AGAT mutant was measured in patient-derived immortalized lymphocytes using stable isotopes of arginine and glycine. The effect of creatine on GATM expression was assessed in human kidney cells and organoids. Several family members from two unrelated families were diagnosed with Fanconi syndrome and had the c.1022C>T (p. P341L) variant in GATM. Two affected individuals in both families had moderately reduced plasma GAA levels. In comparison to wild-type cells, GAA synthesis by patient-derived GATMP341L+/− lymphoblastoid cell lines (LCL) was reduced, but not absent as in GATM cells from a patient with creatine deficiency syndrome. In vitro studies on human kidney organoids revealed reduced AGAT expression after treatment with creatine. Finally, we showed in one patient that creatine supplementation (5 g daily) substantially increased plasma creatine levels. We report low plasma and urine GAA in patients with autosomal dominant GATM-FS and show that creatine downregulates AGAT in human kidney cells.
AB - Autosomal dominant Fanconi syndrome due to a GATM variant (GATM-FS), causes accumulation of misfolded arginine-glycine amidinotransferase (AGAT) in proximal renal tubules leading to cellular injury. GATM-FS presents during childhood and progresses to end-stage kidney disease (ESKD) in adults. We study creatine metabolism in two individuals of unrelated families with a known GATM variant and the effect of creatine supplementation in kidney organoids. Plasma and urine metabolites were measured by mass spectrometry. Brain creatine was assessed by magnetic resonance spectroscopy (MRS). Guanidinoacetate (GAA) synthesis by the AGAT mutant was measured in patient-derived immortalized lymphocytes using stable isotopes of arginine and glycine. The effect of creatine on GATM expression was assessed in human kidney cells and organoids. Several family members from two unrelated families were diagnosed with Fanconi syndrome and had the c.1022C>T (p. P341L) variant in GATM. Two affected individuals in both families had moderately reduced plasma GAA levels. In comparison to wild-type cells, GAA synthesis by patient-derived GATMP341L+/− lymphoblastoid cell lines (LCL) was reduced, but not absent as in GATM cells from a patient with creatine deficiency syndrome. In vitro studies on human kidney organoids revealed reduced AGAT expression after treatment with creatine. Finally, we showed in one patient that creatine supplementation (5 g daily) substantially increased plasma creatine levels. We report low plasma and urine GAA in patients with autosomal dominant GATM-FS and show that creatine downregulates AGAT in human kidney cells.
KW - Fanconi syndrome
KW - GATM
KW - arginine-glycine amidinotransferase (AGAT)
KW - chronic kidney disease
KW - creatine
KW - guanidinoacetate
KW - kidney organoids
UR - http://www.scopus.com/inward/record.url?scp=85208936880&partnerID=8YFLogxK
U2 - 10.1002/jmd2.12442
DO - 10.1002/jmd2.12442
M3 - Article
C2 - 39544690
AN - SCOPUS:85208936880
SN - 2192-8304
VL - 65
SP - 341
EP - 353
JO - JIMD Reports
JF - JIMD Reports
IS - 5
ER -