INF2 Mutations in Charcot-Marie-Tooth Disease with Glomerulopathy

被引：212

作者：

Boyer, Olivia ^{[1
,4
,11
]}

Nevo, Fabien ^{[1
,11
]}

Plaisier, Emmanuelle ^{[2
,7
,12
]}

Funalot, Benoit ^{[16
,17
,18
]}

Gribouval, Olivier ^{[1
,11
]}

Benoit, Genevieve ^{[1
,26
]}

Cong, Evelyne Huynh ^{[1
,11
]}

Arrondel, Christelle ^{[1
,11
]}

Tete, Marie-Josephe ^{[1
,11
]}

Montjean, Rodrick ^{[1
,11
]}

Richard, Laurence ^{[16
,17
,18
]}

Karras, Alexandre ^{[8
,11
]}

Pouteil-Noble, Claire ^{[19
,20
]}

Balafrej, Leila ^{[28
]}

Bonnardeaux, Alain ^{[27
]}

Canaud, Guillaume ^{[5
,11
]}

Charasse, Christophe ^{[22
]}

Dantal, Jacques ^{[23
]}

Deschenes, Georges ^{[9
,13
]}

Deteix, Patrice ^{[24
]}

Dubourg, Odile ^{[10
]}

Petiot, Philippe ^{[21
]}

Pouthier, Dominique ^{[29
]}

Leguern, Eric ^{[3
,12
,14
]}

Guiochon-Mantel, Anne ^{[25
]}

Broutin, Isabelle ^{[11
,15
]}

Gubler, Marie-Claire ^{[1
,11
]}

Saunier, Sophie ^{[1
,11
]}

Ronco, Pierre ^{[2
,7
,12
]}

Vallat, Jean-Michel ^{[16
,17
,18
]}

Angel Alonso, Miguel ^{[30
]}

Antignac, Corinne ^{[1
,6
,11
]}

Mollet, Geraldine ^{[1
,11
]}

机构：

[1] Hop Necker Enfants Malad, AP HP, INSERM, U983, F-75015 Paris, France

[2] Hop Necker Enfants Malad, AP HP, Unite 702, F-75015 Paris, France

[3] Hop Necker Enfants Malad, AP HP, Unite 975, F-75015 Paris, France

[4] Hop Necker Enfants Malad, AP HP, Serv Nephrol Pediat, F-75015 Paris, France

[5] Hop Necker Enfants Malad, AP HP, Serv Transplantat & Soins Intensifs, F-75015 Paris, France

[6] Hop Necker Enfants Malad, AP HP, Serv Genet, F-75015 Paris, France

[7] Hop Tenon, AP HP, Serv Nephrol & Dialyses, F-75970 Paris, France

[8] Hop Europeen Georges Pompidou, AP HP, Serv Nephrol, Paris, France

[9] Hop Robert Debre, AP HP, Serv Nephrol Pediat, F-75019 Paris, France

[10] Hop La Pitie Salpetriere, AP HP, Inst Myol, Paris, France

[11] Univ Paris 05, Paris, France

[12] Univ Paris 06, Paris, France

[13] Univ Paris Diderot, Paris, France

[14] CNRS, Unite 7225, Paris, France

[15] Lab Cristallog & RMN Biol, Paris, France

[16] CHU, Lab Neurol, Limoges, France

[17] CHU, Serv Neurol, Limoges, France

[18] Univ Limoges, Limoges, France

[19] Univ Lyon, Lyon, France

[20] Ctr Hosp Lyon Sud, Serv Nephrol, Lyon, France

[21] Hop Croix Rousse, Serv Neurol, F-69317 Lyon, France

[22] Ctr Hosp St Brieuc, St Brieuc, France

[23] CHU Hotel Dieu, Serv Nephrol & Immunol Clin, Nantes, France

[24] Univ Auvergne, CHU Gabriel Montpied, Clermont Ferrand, France

[25] Univ Paris 11, CHU Bicetre, Le Kremlin Bicetre, France

[26] Univ Montreal, CHU St Justine, Serv Nephrol Pediat, Montreal, PQ, Canada

[27] Hop Maison Neuve Rosemont, Ctr Rech Guy Bernier, Montreal, PQ H1T 2M4, Canada

[28] Ctr Nephrol & Hemodialyse Riad, Rabat, Morocco

[29] Ctr Hosp Luxembourg, Serv Nephrol, Luxembourg, Luxembourg

[30] Univ Autonoma Madrid, Ctr Biol Mol Severo Ochoa, Consejo Super Invest Cient, Madrid, Spain

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2011年 / 365卷 / 25期

关键词：

MEDIATED TRANSPORT; EPITHELIAL-CELLS; MYELIN; PROTEIN; FORMIN; GENE; RHO; GLOMERULOSCLEROSIS; NEPHROPATHY; NEUROPATHY;

D O I：

10.1056/NEJMoa1109122

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Charcot-Marie-Tooth neuropathy has been reported to be associated with renal diseases, mostly focal segmental glomerulosclerosis (FSGS). However, the common mechanisms underlying the neuropathy and FSGS remain unknown. Mutations in INF2 were recently identified in patients with autosomal dominant FSGS. INF2 encodes a formin protein that interacts with the Rho-GTPase CDC42 and myelin and lymphocyte protein (MAL) that are implicated in essential steps of myelination and myelin maintenance. We therefore hypothesized that INF2 may be responsible for cases of Charcot-Marie-Tooth neuropathy associated with FSGS. METHODS We performed direct genotyping of INF2 in 16 index patients with Charcot-Marie-Tooth neuropathy and FSGS who did not have a mutation in PMP22 or MPZ, encoding peripheral myelin protein 22 and myelin protein zero, respectively. Histologic and functional studies were also conducted. RESULTS We identified nine new heterozygous mutations in 12 of the 16 index patients (75%), all located in exons 2 and 3, encoding the diaphanous-inhibitory domain of INF2. Patients presented with an intermediate form of Charcot-Marie-Tooth neuropathy as well as a glomerulopathy with FSGS on kidney biopsy. Immunohistochemical analysis revealed strong INF2 expression in Schwann-cell cytoplasm and podocytes. Moreover, we demonstrated that INF2 colocalizes and interacts with MAL in Schwann cells. The INF2 mutants perturbed the INF2-MAL-CDC42 pathway, resulting in cytoskeleton disorganization, enhanced INF2 binding to CDC42 and mislocalization of INF2, MAL, and CDC42. CONCLUSIONS INF2 mutations appear to cause many cases of FSGS-associated Charcot-Marie-Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system. These findings provide new insights into the pathophysiological mechanisms linking formin proteins to podocyte and Schwanncell function. (Funded by the Agence Nationale de la Recherche and others.)

引用

页码：2377 / 2388

页数：12

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