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Neurological involvement in monogenic podocytopathies

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Abstract

Genetic studies of hereditary nephrotic syndrome (NS) have identified more than 50 genes that, if mutated, are responsible for monogenic forms of steroid-resistant NS (SRNS), either isolated or syndromic. Most of these genes encode proteins expressed in the podocyte with various functions such as transcription factors, mitochondrial proteins, or enzymes, but mainly structural proteins of the slit diaphragm (SD) as well as cytoskeletal binding and regulator proteins. Syndromic NS is sometimes associated with neurological features. Over recent decades, various studies have established links between the physiology of podocytes and neurons, both morphologically (slit diaphragm and synapse) and functionally (signaling platforms). Variants in genes expressed in different compartments of the podocyte and neurons are responsible for phenotypes associating kidney lesions with proteinuria (mainly Focal and Segmental Glomerulosclerosis (FSGS) or Diffuse Mesangial Sclerosis (DMS)) and central and/or peripheral neurological disorders. The Galloway-Mowat syndrome (GAMOS, OMIM#251300) associates neurological defects, microcephaly, and proteinuria and is caused by variants in genes encoding proteins of various functions (microtubule cytoskeleton regulation (WDR73), regulation of protein synthesis via transfer RNAs (KEOPS and WDR4 complexes)). Pierson syndrome (OMIM#609049) associating congenital nephrotic syndrome and central neurological and ophthalmological anomalies is secondary to variants in LAMB2, involved in glomerular and ocular basement membranes. Finally, Charcot-Marie-Tooth-FSGS (OMIM#614455) combines peripheral sensory-motor neuropathy and proteinuria and arises from INF2 variants, resulting in cytoskeletal polymerization defects. This review focuses on genetic syndromes associating nephrotic range proteinuria and neurological involvement and provides the latest advances in the description of these neuro-renal disorders.

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  1. Service de Néphrologie Pédiatrique, AP-HP, Centre de Référence de maladies rénales rares de l’enfant et de l’adulte (MARHEA), Hôpital Necker - Enfants Malades, 149 Rue de Sèvres, 75015, Paris, France

    Olivia Boyer

  2. Institut Imagine, Laboratoire des maladies rénales héréditaires, INSERM UMR 1163, Université de Paris, Paris, France

    Olivia Boyer, Géraldine Mollet & Guillaume Dorval

  3. Service de Génétique Moléculaire, AP-HP, Hôpital Necker-Enfants Malades, Paris, France

    Guillaume Dorval

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1. a, c, e. In this peripheral neuropathy, deep tendon reflexes are usually reduced; 2. a, b, e; 3. b, c, e.

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Boyer, O., Mollet, G. & Dorval, G. Neurological involvement in monogenic podocytopathies. Pediatr Nephrol 36, 3571–3583 (2021). https://doi.org/10.1007/s00467-020-04903-x

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