TRPC6 Mutations in Children with Steroid-Resistant Nephrotic Syndrome and Atypical Phenotype

被引:80
作者
Gigante, Maddalena [1 ,2 ]
Caridi, Gianluca [4 ]
Montemurno, Eustacchio [1 ,2 ]
Soccio, Mario [2 ]
d'Apolito, Maria [3 ]
Cerullo, Giuseppina [1 ]
Aucella, Filippo [5 ]
Schirinzi, Annalisa [1 ,2 ]
Emma, Francesco [6 ]
Massella, Laura [6 ]
Messina, Giovanni [7 ,8 ]
De Palo, Tommaso [7 ,8 ]
Ranieri, Elena [1 ,2 ]
Ghiggeri, Gian Marco [4 ]
Gesualdo, Loreto [1 ]
机构
[1] Univ Foggia, Dept Biomed Sci, I-71100 Foggia, Italy
[2] Univ Foggia, Interdept Res Ctr BioAgromed, I-71100 Foggia, Italy
[3] Univ Foggia, Inst Pediat, I-71100 Foggia, Italy
[4] G Gaslini Inst Children, Lab Pathophysiol Uremia, Div Nephrol, Genoa, Italy
[5] Casa Sollievo Sofferenza Hosp, IRCCS, Div Nephrol, San Giovanni Rotondo, Italy
[6] Bambino Gesu Childrens Hosp & Res Inst, Dept Nephrol & Urol, Rome, Italy
[7] Univ Bari, Giovanni XXIII Hosp, Div Nephrol, Bari, Italy
[8] Univ Bari, Dept Biomed Dev Age, Bari, Italy
来源
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2011年 / 6卷 / 07期
关键词
GLOMERULAR PROTEIN; SLIT DIAPHRAGM; LARGE COHORT; CHANNELS; NEPHRIN; NEPHROPATHY; ACTIVATION; GENE;
D O I
10.2215/CJN.07830910
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background and objectives Mutations in the TRPC6 gene have been recently identified as the cause of late-onset autosomal-dominant focal segmental glomerulosclerosis (FSGS). To extend the screening, we analyzed TRPC6 in 33 Italian children with sporadic early-onset SRNS and three Italian families with adult-onset FSGS. Design, setting, participants, & measurements TRPC6 mutation analysis was performed through PCR and sequencing. The effects of the detected amino acid substitutions were analyzed by bioinformatics tools and functional in vitro studies. The expression levels of TRPC6 and nephrin proteins were evaluated by confocal microscopy. Results Three heterozygous missense mutations (c.374A>G_p.N125S, c.653A>T_p.H218L, c.2684G>T_p.R895L) were identified. The first new mutation, p.H218L, was found in a 18-year-old boy who presented a severe form of FSGS at the age of 8 years. The second, p.R895L, a new de novo mutation, was identified in a girl with collapsing glomerulosclerosis at the age of 2 years. The former mutation, p.N125S, was found in two siblings with early-onset steroid-resistant nephrotic syndrome (SRNS) at the ages of 4 and 14 years. Renal immunofluorescence revealed upregulated expression of TRPC6 and loss of nephrin in glomeruli. The intracellular calcium concentrations were significantly higher in the cells expressing all mutant TRPC6 channels compared with cells expressing wild-type TRPC6. Conclusions Our findings suggest that TRPC6 variants can also be detected in children with early-onset and sporadic SRNS (4 of 33 patients). Moreover, in one patient a new de novo TRPC6 mutation was associated with a rare severe form of childhood collapsing glomerulosclerosis with rapid progression to uremia. Clin J Am Soc Nephrol 6: 1626-1634, 2011. doi: 10.2215/CJN.07830910
引用
收藏
页码:1626 / 1634
页数:9
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