quels progrès dans la recherche sur les maladies rénales ...¨s-de-la... · the kidney diseases...

Quels progrès dans la recherche sur les maladies rénales

génétiques en pédiatrie ?

Denis Morin

Montpellier

Recherche clinique en pédiatrie

• Faibles nombres de patients parfois

– Études multicentriques +++

• Considérations éthiques

– Recherche qu’on ne peut pas faire chez des patients adultes

• Importances des protocoles (PHRC, autres,..)

Néphrologie Pédiatrique

Maladies kystiques

Tubulopathies

Glomérulopathies

Basalopathies

Autres…

SHU atypique

Maladies rénales kystiques

• Polykystose dominante

• Polykystose récessive

• Maladie kystique liée à TCF2

Polykystose dominante

• Diagnostic anténatal possible

– Echographie / IRM

• Questions concernant la prise en charge

– Surveillance simple de loin en loin ?

– Possibilités d’attitudes thérapeutiques préventives à l’image de ce qui existe pour les adultes ?

Polykystose récessive

• Maladie rare 1/25 000 naissances

• Transmission autosomique récessive

• Expression anténatale fréquente

– Mise en évidence de gros reins hyperéchogènes

– Parfois retentissement fœtal

• Oligoamnios

• Diagnostic génétique possible

– Etude de corrélations génotype/phénotype

• Pas de résultats probants en terme de conseil génétique (CJASN 2010)

Polykystose récessive

• Grande variabilité d’expression clinique

– Atteinte rénale

– Atteinte hépatique

• Prise en charge symptomatique

– Traitement anti-HTA

– Prise en charge insuffisance rénale chronique

• Place d’une approche thérapeutique spécifique visant à limiter le développement des kystes ?

Pathologie kystique liée à des mutations du gène TCF2/HNF1b

Syndrome d’Alport

Syndrome d’Alport

• Basalopathie héréditaire

- Forme liée à l’X

- Forme autosomique récessive

- Forme autosomique dominante

- Anomalie chaines a du collagène

• Evolution

⁻ Protéinurie

⁻ HTA

⁻ Insuffisance rénale

Syndrome d’Alport

Heidet L , Gubler M JASN 2009;20:1210-1215

©2009 by American Society of Nephrology

Copyright ©2009 American Society of Nephrology

Heidet, L. et al. J Am Soc Nephrol 2009;20:1210-1215

Figure 2. Schematic algorithm in case of Alport syndrome suspicion because of hematuria {+/-} proteinuria

Syndrome d’Alport

Cyclosporine A treatment in patients with Alport syndrome: a single-center experience.

Massela et al Ped Nephrology 2010

“Our data do not support the use of CsA therapy for proteinuric patients with AS, particularly if they have chronic renal failure”

Syndrome d’Alport

• Efficacy and safety of losartan in children with Alport syndrome results from a subgroup analysis of a prospective, randomized, placebo- or amlodipine-controlled trial.

Webb J and col. Nephrol Dial Transplant. 2011 Aug;26(8):2521-6

• Inhibition du système rénine angiotensine

– Effet anti-protéinurique

– Anti-cytokine

– Inhibition de la production de collagène

– Inhibition de la fibrose tubulo-interstitielle

http://www.ncbi.nlm.nih.gov/pubmed/21285125

Syndrome d’Alport

• Nephroprotective effect of the HMG-CoA-reductase inhibitor cerivastatin in a mouse model of progressive renal fibrosis in Alport syndrome

• Koepke ML et al . NDT 2007

– Action antio-fibrotique

– Moindre infiltrat de cellules inflammatoires

– Intérêt d’un traitement précoce en pédiatrie ?

Syndrome d’Alport

• Modèle animal de souris COL4A3 -/-

• Intérêt de la transplantation médullaire ?

– Recrutement de cellules aptes à devenir des podocytes et des cellules mésangiales

– A confirmer

Syndrome hémolytique et urémique


• Forme post-diarrhéique : typique

– Nourrisson avant 2 ans

– Infection à E.Coli entéropathogène

– Anémie, thrombopénie, IRA

– Dialyse dans 50% des cas

– Pronostic dominé par atteinte neurologique

– Présence schizocytes


• Forme atypique

– Age de début variable

• Formes néonatales

– Pas de contexte infectieux

• SHU D-

– Début plus insidieux

• HTA plus fréquente

– Risque de rechute

SHU atypique

• Déficit en ADAMTS 13

• Anomalie du métabolisme Vitamine B12

• Anomalie de la régulation de protéines du système du complément

Système du complément

SHU atypique et anomalies du complément

• Différents facteurs en cause

– MCP ,

– C3, H, I, B

• Etude de l’expression de MCP

• Dosages du C3 et des facteurs H, I, B

• Anticorps anti-H ?

• Génotypage même si taux plasmatiques normaux

– anomalies qualitatives ?

SHU atypique et anomalies du complément Prise en charge

• Traitement symptomatique : HTA, IRA, Anémie,…

• Traitement « spécifique » récent

– Plasmathérapie débutée dès que possible

• Perfusion de plasma

• Echanges plasmatiques +++

• Questions :

– Combien de temps ?

– Problèmes abords vasculaires


• A long terme ?

– Echanges plasmatiques

– Anticorps monoclonal anti-C5

– Concentré de facteur H

• Si insuffisance rénale terminale

– Transplantation rénale + EP

– Transplantation combinée foie – rein

– Concentré de facteur H

– Anticorps monoclonal anti-C5


• Actuellement

• Protocole de prise en charge des SHU atypique de l’enfant par Eculizumab

SHU typique et activation du système du complément

• « Epidémie » de SHU post-diarrhéique en 2011 (Allemagne, Bordeaux, Lille)

• Formes avec atteinte neurologique

– Intérêt du traitement par Eculizumab dans les formes sévère de SHU typique

Cystinose

PHYSIOPATHOLOGIE

• Défaut du transporteur

lysosomal de cystine:

CYSTINOSINE

• Gène CTNS (23 kb)

• Transmission autosomique récessive: 1/200 000

naissances vivantes

• Accumulation et cristallisation

intralysosomiale de cystine = Maladie systémique

W Gahl, 2002

Cystinose - Traitement

• Cystagon = chlorydrate de cystéamine

– 10-50 mg/Kg/jour sans dépasser 1300 mg/m2

– En 4 prises dont une nocturne +++

– Cible thérapeutique

– Cystine intraleucocytaire < 1 nmole/mg protéine

– Collyre cystéamine

• Traitement symptomatique du syndrome de Fanconi

Cystinose - Evolution

Age distribution of patients starting renal replacement therapy (RRT) in different eras.

Van Stralen K J et al. CJASN 2011;6:2485-2491

©2011 by American Society of Nephrology

Cystinose - Traitement

• Etude « Raptor »

– Vise à étudier la tolérance et l’efficacité d’une forme galénique nouvelle de cystéamine qui permettra une prise toutes les 12 heures

– Etude qui s’est déroulé aux USA et en Europe

– Doit permettre une diminution des prises de médicaments, source d’une meilleure observance

• Equivalence entre Raptor et Cystagon

– Démarche en vue d’obtenir l’AMM en cours

Syndromes néphrotiques


Machuca E et al. Hum. Mol. Genet. 2009;18:R185-R194

© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions,

please email: [email protected]


• SN génétiquement déterminés

• Néphrose lipoïdique


• Début précoce, parfois néonatal, peut être tardif

• ATCD familiaux

• Transmission AD ou AR

• Corticorésistance

• Pas de récidive après transplantation rénale

• Etude génétique nécessaire pour affirmer le diagnostic

Diaphragme de fente / Podocytes




Age de début du SN selon le type d’anomalie génétique





• SN génétiquement déterminés

• Néphrose lipoïdique

Néphrose lipoïdique

• 1 an à 12 ans

• Protéinurie / rechutes

• Lésion glomérulaires minimes

• Pronostic dominé par évolution

– Corticosensibilité ?

– Corticodépendance ?

– Corticorésistance ?

• Probablement « polygénique »

Néphrose

Etude Néphromycy (V Baudoin)

• Vise à comparer l’efficacité et la tolérance de deux thérapeutiques utilisées dans la néphrose cortico-dépendante

– Cyclophosphamide

– Mycophénolate mophétil

• Débutée début 2011

Néphrose Traitement

Néphrose Traitement

• Etude NEPHRUTIX

– Vise à mesure l’efficacité et la tolérance du Rituximab dans certains cas de néphrose cortico-dépendante et antiocalcineurine dépendante

– Rituximab :

• antiCD20

• Action sur les B lymphocytes

• Efficacité / risques

Conclusion

• Beaucoup d’autres sujets

– Tubulopathies

– Oxalose

– Cystinurie

– …

Diabète Insipide Néphrogénique congénital

DINc

• Pathologie rare ++

• Expression néonatale précoce

– Polyurie – perte de poids – déshydratation

– Hypernatrémie – trouble de concentration des urines

– Résistance du tubule rénal à l’action de la vasopressine

DINc - Génétique

Récépteur V2 de la vasopressine Aquaporine 2

Sexe masculin Expression dans les deux sexes

Femme transmettrice

Diabète insipide néphrogénique congénital

• Traitement symptomatique

– Hydratation : NEDC parfois

– AINS

– Hydrochlorothiazide

• Traitement spécifique en cas de mutation du RV2 : molécules chaperonnes ?

Molécule Chaperonne

Bouvier et al 2006

Effets chez les patients ?

Efficacité fonction de la nature des mutations en cause

Mais….

Bouvier et al 2006

V2

A294P

L44P

R337X

Recherche de pharmacochaperones agonistes Expression à la surface cellulaire-Microscopie confocale

Contrôle MCF57 18H

JASN 2009

MCF = Pharmacochaperones Agonistes pour A294P et L44P

Pas d’effet sur le mutant R337X malgré une restauration à la membrane

Effet agoniste des MCF sur les récepteurs DNIc

JASN 2009

Autre pathologie lié à une mutation du Récepteur V2 de la

vasopressine : Syndrome d’antidiurèse d’origine

néphrogénique

NSIAD décrit en 2005

NSIAD H

A

Y M G V M Q L Y K V A

L I M Y S S A

R

D

R

L T M

R I A

120

135

125

L

C H DINc

C L

TM3

e2

i2

NSIAD

• Signes cliniques: variabilité phénotypique – Crises convulsives ++, âge d’apparition variable

– Mais aussi patients asymptomatiques

• Signes biologiques: – Hyponatrémie

– Baisse de l’osmolalité plasmatique

– Osmolalité urinaire inadaptée anormalement élevée

– Absence ou faible sécrétion de vasopressine

– Réponse anormale à une épreuve de charge hydrique

• Principal diagnostic différentiel: SIADH

NSIAD

• Possibilité d’évolution neurologique péjorative si absence de diagnostic et récidive des convulsions

• Circonstance déclenchant la symptomatologie: ingestion excessive d’eau (chaleur, relais de l’allaitement maternel)

• Traitement: – Restriction hydrique +/- urée

– Inefficacité des antagonistes non peptidiques du récepteur V2

• Femmes transmettrices: – Souvent antidiurèse inappropriée

– Parfois signes cliniques ou biologiques

NSIAD

• Pathologie de description récente

• Variabilité phénotypique patients et femmes transmettrices

• Fréquence probablement sous-estimée

• Nécessité d’une information médicale ciblée pour permettre le diagnostic

• Avancées dans la compréhension des mécanismes physiopathologiques

• Meilleure appréhension de la structure du récepteur V2

OMIM Gene/locus Genetic Implicated molecule

Protein expression in renal tubule

Principal featuresa

Other features

Antenatal Bartter syndrome

601678 SLC12A1/15q21.1

Type I Na-K-2Cl cotransporter

TAL

Polyhydramnios, prematurity, nephrocalcinosis, polyuria, failure to thrive

241200 KCNJ1/11q24 Type II Kir 1.1 potassium channel

TAL and CCD

Transitory hyperkalaemia in neonatal period in most patients

602522 CLCNKB/1p36 Type III ClC-Kb chloride channel

TAL and DCT Nephrocalcinosis in some patients

Antenatal Bartter syndrome with SNHL

607364 BSND/1p31 or CLCNKA–CLCNKB/1p36

Type IV

Barttin ClC-Ka and ClC-Kb chloride channels

TAL and DCT tAL, TAL, DCT and CCD

CRI with some Barttin mutations

Classic Bartter syndrome

602522 CLCNKB/1p36 SLC12A3/16q13

Type III

ClC-Kb chloride channel Na-Cl cotransporter

TAL and DCT DCT

Severe to mild salt wasting with or without nephrocalcinosis

Sometimes hypomagnesaemia

Gitelman Syndrome

263800 SLC12A3/16q13 CLCNKB/1p36

Na-Cl cotransporter ClC-Kb chloride channel

DCT TAL and DCT

Hypomagnesaemia, hypocalciuria

Sometimes polyuria, failure to thrive or growth hormone deficiency

Plasma potassium, chloride and bicarbonate concentration at diagnosis in patients with

antenatal and neonatal Bartter syndrome according to the gene involved.

Brochard K et al. Nephrol. Dial. Transplant. 2009;24:1455-

1464

© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights

reserved. For Permissions, please e-mail: [email protected]

Growth under treatment (water and electrolyte + indomethacin) according to the gene

involved.

Brochard K et al. Nephrol. Dial. Transplant. 2009;24:1455-

1464


reserved. For Permissions, please e-mail: [email protected]

The kidney diseases discussed above can be life-threatening and most have limited, often unsuccessful, treatment options. Many patients with MPGN and aHUS experience recurrent episodes that eventually lead to end-stage renal failure.40,57,84 Even when kidney transplants are successful, diseases that are caused by systemic factors such as mutated fH, C3 and fB can present again and the outcome is often fatal.72,103 In such situations, combined kidney and liver transplantation may be the only way to correct the underlying defects, and success with such an approach has been described in the literature but the high risk for adverse events in such procedures makes this a less desirable option.104,105 By the same principle, kidney transplantation may be an acceptable option for end-stage aHUS patients whose diseases are attributable to mutations in the membrane regulator MCP.91,106 Given the well-established role of complement in the pathogenesis of these kidney diseases, it is envisioned that systemic or targeted local complement inhibition may represent a promising therapeutic strategy. In this context, the recent approval and successful clinical application of a first-in-class complement inhibitor Eculizumab, a humanized anti-C5 monoclonal antibody,107 for treatment of the complement-mediated disease paroxysmal nocturnal haemaglobinuria108–110 is particularly encouraging. Based on a number of animal studies in which C5 deficiency or C5-blocking antibodies reduced renal injury,59,69,111 it may be anticipated that Eculizumab will prove to be efficacious for some, if not all, complement-mediated kidney disorders as well. Indeed, two case reports on the successful treatments of paediatric aHUS patients with Eculizumab have already appeared in the literature112,113 and clinical trials on the use of Eculizumab in aHUS are currently underway.114 Other complement-based therapeutic strategies include chemical and biological agents that target additional complement components. A chemical inhibitor for C3aR and two antagonists for C5aR, a cyclic hexapeptide and a recombinant C5a analogue, have been developed and shown to effectively block anaphylatoxin-mediated inflammatory injury in a variety in vitro and in vivo studies including models of renal IRI and transplantation.115–118 A synthetic peptide, named Compstatin, with potent human C3-inhibiting activity has also been developed by phage display and shown to effectively shut down human complement activation in several experiments including an ex vivo model of hyperacute rejection of kidney xenotransplantation model.119–121 Compstatin is currently being evaluated in clinical trials for the treatment of AMD, a disease that also implicates abnormal AP complement activation.122 One of the concerns of targeting C3 with agents like Compstatin is that they obliterate the complement system completely, potentially compromising host defence and leaving the patients susceptible to infection. Because the AP complement is principally involved in many of the complement-mediated diseases, efforts have also been made to develop inhibitors that target the AP only. For example, two anti-C3b mAbs that specifically inhibit the AP C3 convertase with no activity on classical and lectin pathway complement activation have been described recently.123,124 A third area of promising research for treating complement-mediated kidney injury is the creation of soluble recombinant forms of complement regulatory proteins. Several studies have shown that administering a soluble form of CR1 or Crry can reduce renal injury125,126 and such proteins have an extended half-life when fused to an Ig Fc domain.127 More recently, strategies have been developed to target the recombinant protein to sites of injury. He et al. targeted recombinant regulatory proteins to the kidney using an Ag-specific single chain Ab fragment.128 In other efforts, the inhibitors were directed to sites of complement activation with the design of a fusion protein consisting the C3d-binding domain of CR2 and a regulatory protein partner, either Crry (CR2-Crry) or the SCR1-5 region of fH (CR2-fH).129 In one study of MRL/lpr mice, which are prone to autoimmune glomerulonephritis and vasculitis, CR2-Crry ameliorated disease symptoms compared with untreated mice.130 Studies with these recombinant proteins have also been performed for other diseases with a strong AP component, including intestinal IRI and collagen-induced arthritis.129,131 These studies demonstrated

http://onlinelibrary.wiley.com/doi/10.1111/j.1440-1797.2010.01373.x/full

























The basic defect in Alport syndrome is either the lack, in the mature GBM, of the 3- 4- 5(IV) network and its failure to replace the 1- 2 network,

which is known to be less resistant to proteolysis, or the presence of a defective 3- 4- 5(IV) network. There are several animal models for AS, in

dogs and mice that faithfully recapitulate autosomal and X-linked forms of the disease. They have brought novel data to the understanding of the

mechanisms responsible for the progression of AS nephropathy and in the elaboration of future therapies. The re-expression of the 3(IV) chain in

Col4a3-/- mice, for example, was shown to restore the expression of 4 and 5 (IV), thus demonstrating that the expression of all three 3- 4- 5(IV)

chains is required for network assembly.12 The downstream mechanisms responsible for progressive alteration of the GBM and renal failure are not

fully understood. In young Alport mice, the ultrastructurally normal GBM is known to already be abnormally permeable.13 The concomitant

accumulation of mRNAs encoding TGFβ1 and extracellular matrix components in human and mouse Alport podocytes are thought to reflect key

events in renal disease progression.14 Blocking the TGFβ1 pathway prevents GBM thickening in Alport mice.15

The role of metalloproteinases in Alport disease has been underlined by recent studies. Increased expression of MMP2, MMP3, and MMP9 has

been described, both at the transcriptional and the protein level, in AS kidneys in humans, mice, and dogs.16,17 Such MMP up-regulation is not

unique to Alport nephropathy. However, AS kidney basement membranes were shown to be more readily degradable in vitro by collagenase,

elastase, and cathepsins, compared with normal kidney basement membranes,18 and this is thought to be due to the lack of the highly cross linked

3- 4- 5(IV) network. Blocking simultaneously at least MMP2, MMP3, and MMP9 in Col4a3-/- mice delays the progression of the disease if treatment

is given before development of GBM injury and occurrence of proteinuria in a C57BL6 genetic background.16 In addition, a recent study found an

increase of MMP12 expression in podocytes of humans, mice, or dogs affected with AS, possibly linked to MCP1-mediated activation of the

podocyte CCR2 receptor.19 Either MMP12 inhibitor or CCR2 receptor antagonist attenuates the GBM thickening in Col4a3-/- mice.19

Pharmacologic therapeutic approaches have been tested in animal models and in humans. Cyclosporine A was found to delay progression of renal

failure in humans and dogs in initial studies.20,21 However, cyclosporine is also found to be rapidly associated with nephrotoxicity, thereby precluding

its long-term use.22 Angiotensin-converting enzyme inhibitors and/or angiotensin 2 type 1 receptor antagonists reduce urinary protein excretion and

preserve glomerular filtration in dogs affected with X-linked AS, in Col4a3-/- mice,23 and in a few pediatric patients.24 Larger controlled studies are

necessary in humans to clarify the long-term benefit of the treatment and the nature and doses of drugs that are effective. Also, criteria for micro- or

macroalbuminuria for starting renoprotective treatment by blockade of the renin-angiotensin system remain to be precisely determined. In Alport

mice, chemokine receptor-1 blockade as well as statin treatment improves survival and renal lesions.25 Finally, bone marrow transplantation of

Col4a3-/- mice shows recruitment of bone marrow cells as future podocytes and mesangial cells, partial restoration of the expression of the 3- 4-

5(IV) network, and clinical and histologic improvement.26–28 However, a recent study suggested that irradiation, which preceded bone marrow

transplantation, may improve the survival of Col4a3-/- mice by itself, through as yet unidentified mechanisms.29

Overt anti-GBM nephritis occurs in only 3 to 5% of transplanted Alport patients.30 The risk of graft loss is very high, and treatment with

plasmapheresis and cyclophosphamide has shown limited benefit. The risk of recurrence on subsequent transplantation is very high. This

complication is more likely to occur in patients with deletions or frameshift mutations, who do not express the 3 4 5(IV) GBM network. However,

many patients with COL4A5 deletion have been successfully transplanted, without developing anti GBM nephritis, and predictive factors for

developing the disease are currently unknown.

http://jasn.asnjournals.org/cgi/content/full/20/6/1210




















Cemara

1. Determination of C3, CFH, CFI and CFB levels, expression of MCP and screening for anti-CFH antibodies is indicated for all patients with aHUS. Normal C3 level does not eliminate the presence of CFH or CFI mutation or of anti-CFH antibodies.

2. Genotyping of CFH, CFI and MCP, and if possible CFB and C3, is indicated for all patients with aHUS, even if plasma levels are normal.

3. The identified mutation has to be regarded as a risk factor for HUS, not as the direct cause. The association of mutations in several genes is not exceptional. Penetrance of the disease is 50% in patients with a mutation in complement. Therefore, the risk of developing HUS is difficult to predict in family members with the mutation. Intrafamilial genetic heterogeneity exists, suggesting that unknown genetic factors are present.

4. A post-diarrheal onset of HUS can be observed in all groups. Therefore, genotyping must be performed for patients with uncertain diagnosis of D + /STEC + HUS, especially before transplantation. The worst prognosis is in patients with CFH mutation, who are at high risk of ESRD as soon as at first flare or within the year of onset.

5. Plasmatherapy (PE with FFP) should be started as early as possible. Although evidence is lacking, benefit is expected mainly in CFH-mutated patients and in patients with anti-CFH antibodies. Benefit is likely in all other subgroups of aHUS, except the MCP subgroup, where spontaneous remission generally occurs.

6. The risk of graft loss due to HUS recurrence or graft thrombosis is high in patients with CFH and CFI mutations, while it is very low in patients with MCP mutations. Family living donor transplantation is contraindicated, because of the risk of graft loss due to recurrence and the risk that donors themselves might have HUS after donation, due to unknown genetic factors shared with the recipient. Kidney transplantation under pre-, intra- and post-operative intensive plasmatherapy may be successful in some patients. Combined liver and kidney transplantation under pre- and intra-operative plasmatherapy, and post-operative anticoagulation, has been successful in a few patients with CFH mutation. This option will now have to be considered on an individual basis for patients with mutations in other factors synthesized in the liver.

7. Hope for the future relies on therapies which could prevent ESRD, such as CFH concentrate or anti-C5 monoclonal antibodies.


Mache, C. J. et al. Clin J Am Soc Nephrol 2009;4:1312-1316

Figure 1. Clinical course and laboratory findings

Infiltration of CD3-positive T-cells (A–D), F4/80-positive macrophages (E–F) and α-SMA-

positive activated fibroblasts (H–J).

Koepke M et al. Nephrol. Dial. Transplant. 2007;22:1062-

1069


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Klein, J. et al. J Am Soc Nephrol 2010;21:1157-1164

Figure 2. Representative human B1R expression in normal and pathologic human kidney biopsies



Figure 4. Delayed B1Ra treatment reduces renal lesions and improves renal function



Figure 5. B1R blockade inhibits the development of renal fibrosis

Recherche plus fondamentale

Gene Locus Inheritance Protein Functiona Phenotype or Syndrome

Slit-Diaphragm protein complex

NPHS1 19q13.1 AR Nephrin

Main component of the SD. Anchors the SD to the actin cytoskeleton. Modulate signalling events related with actin cytoskeleton dynamics, cell polarity and survival

CNS of the Finnish type. Early-onset SRNS in cases carrying at least one mild mutation

NPHS2 1q25–31 AR Podocin

Scaffold protein linking plasma membrane to the actin cytoskeleton. Modulates mechanosensation

CNS. Early and late onset AR SRNS. Juvenile and adult SRNS in cases bearing the R229Q variant in compound heterozygous state with a pathogenic mutation

PLCE1 10q23 AR Phospholipase Cε1 Involved in cell junction signalling and glomerular development

Early-onset SRNS with DMS and FSGS

CD2AP 6p12.3 AR (?) CD2 associated protein Adapter protein, may anchor the SD to the actin cytoskeleton

Not precisely defined in humans, may cause early-onset SRNS and FSGS. Mice model exhibits a severe phenotype resembling CNS in humans

TRPC6 11q21–22 AD TRPC6

Receptor-activated non-selective calcium permeant cation channel. Involved in mechanosensation

Adult-onset SRNS with FSGS

ACTN4 19q13 AD α-actinin-4 F-actin cross-linking protein

Late-onset SRNS with incomplete penetrance and slow progression to ESRD

MYH9 22q12.3 complex NMMHC-A Cellular myosin that appears to play a role in cytokinesis and cell shape

High risk haplotypes associated with increased risk of FSGS and ESKD in African-Americans

Nuclear proteins

LMX1B 9q34.1 AD LIM/homeobox protein LMX1B

Podocyte and GBM development and maintenance

Nail-patella syndrome. NS in 40% of cases

SMARCAL1 2q35 AR hHARP ATP-dependent annealing helicase that rewind stably unwound DNA

Schimke immuno-osseus dysplasia

WT1 11p13 AD Wilms’ tumour 1 Zinc finger transcription factor that functions both as a tumour suppressor and as a critical regulator of kidney and gonadal development

Denys–Drash syndrome, Frasier syndrome, WAGR syndrome, isolated FSGS and DMS

Actin cytoskeleton components

Glomerular basement membrane proteins

LAMB2 3p21 AR Laminin-β2 GBM component, scaffold for type IV collagen assembly. Interactions with integrin α3β1 links the GBM to the actin cytoskeleton

Pierson syndrome

ITGB4 17q25.1 AR Integrin-β4 Cell-matrix adhesion, critical structural role in the hemidesmosome of epithelial cells

Epidermolysis bullosa. Anecdotic cases presenting with NS and FSGS

Mitochondrial proteins

COQ2 4q21–q22 AR Polyprenyltransferase CoQ10 biosynthesis, which transfers electrons from the mitochondrial respiratory chain

COQ10 deficiency, early-onset SRNS, with or without encephalomyopathy

PDSS2 6q21 AR Decaprenyl diphosphate synthase-2

CoQ10 biosynthesis, which transfers electrons from the mitochondrial respiratory chain

COQ10 deficiency, Leigh syndrome and SRNS

MTTL1 mtDNA tRNA-LEU Mitochondrial tRNA for leucine

MELAS syndrome. Mitochondrial diabetes, deafness and FSGS, with or without nephrotic syndrome

Lysosomal proteins

SCARB2 4q13–21 AR LIMP II May act as a lysosomal receptor

Action myoclonus renal failure

Light and electron microscopy.

Koepke M et al. Nephrol. Dial. Transplant. 2007;22:1062-

1069


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