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Urine Proteomic Analysis in Cystinuric Children with Renal Stones
Larisa Kovacevic, MD, Hong Lu, PhD, Yegappan Lakshmanan, MD.
Children's Hospital of Michigan, Detroit, MI, USA.

Background: The gene mutations found in children with cystinuria cannot solely explain kidney stone formation, suggesting that specific proteins may serve as promoters of cystine precipitation, aggregation or epithelial adherence. We aimed to identify proteins unique to cystinuria and kidney stone by performing urine proteomic analysis.
Methods: We compared urinary proteomes of 2 children with cystinuria and kidney stones and 2 healthy children (measurements performed in duplicate), using mass spectrometry (MS) total ion current quantification of proteins. Proteins of interest were selected based on the number of assigned peptides that map to a particular protein (more than 5), and unique peptides that have been identified for each protein (more than 2) as a threshold to be well above observed technical variations in MS experiments.
Results: Of the 665 proteins identified by proteomic analysis, 152 proteins were found only in children with cystinuria and kidney stones, 12 of which met the selection criteria (Table). Additionally, these children were found to have 2-4 times higher urinary levels of ceruloplasmin, and lower levels of osteopontin and uromodulin compared to controls.
Accession Number*ProteinMW (kDa)No. of assigned peptides**No. of unique peptides**Sequence coverage
(%)***
ANXA1Annexin A13914/129/832/29
FIBBFibrinogen beta chain56129/9125/2166/49
ITIH2Inter-alpha-trypsin inhibitor10633/8112/1127/16
TRFLLactotransferrin78185/1136/360/6
MMP9Matrix metalloproteinase 97826/159/718/12
PERMMyeloperoxidase8488/619/532/3
PLSLPlastin-27042/814/433/11
PON1Serum paraoxonase4023/749/1448/55
TBA1BTubulin alpha-1B chain509/138/427/15
VIMEVimentin5410/98/421/14
NGALNeutrophil gelatinase-associated lipocalin23110/4010/666/45
TAGL2Transgelin-22213/76/450/33

*Human; **Values presented in each patient
*** % of sequence that has been identified for each protein
Conclusions: Children with cystinuria and kidney stones have a different urinary polypeptide profile compared to healthy controls. These unique proteins merit further investigation. Proteomic analysis may be useful to identify potential disease biomarkers and novel therapeutic targets.


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