Expanding the clinical spectrum of congenital nephrotic syndrome caused by NPHS1 mutations

Abstract

Nephrotic syndrome (NS) is a life-threatening condition when starting within the 3 months after birth [1–3]. Descriptively, NS is classified as congenital (CNS) when manifesting in utero or during the first three months of life, infantile (INS) with onset later during the first year (4–12 months) and childhood when it develops thereafter [1–3]. CNS may be also described as syndromic or isolated, depending on the presence or not of extrarenal malformations including dysmorphic facial features (e.g. microcephaly) [1–3]. The identification over the last decade of disease-causing mutations in various podocyte-expressed proteins has significantly improved early diagnosis, clinical management and genetic counselling of hereditary CNS [1–3]. Mutations in the gene NPHS1 encoding nephrin were found as the most common cause of CNS [4]. Originally known as the Finnish type of CNS (CNF) [5], this autosomal recessive condition is nowadays preferentially called nephrotic syndrome type 1 (NPHS1) is CNS, due to about 100 distinct mutations found in Finnish as well as non-Finnish cohorts [1–3]. The second most frequent gene causing CNS is the podocin (NPHS2) gene [6], first implicated in sporadic cases of childhood steroid-resistant NS with focal glomerulosclerosis [7]. In a recent large cohort of patients with an isolated NS occurring within the first year of life, two-thirds of the cases were due to mutations in either the NPHS1 or the NPHS2 genes [4]. In the remaining cases, the responsible gene was found to be the transcription factor WT1 (WT1) gene, the laminin-beta 2 (LAMB2) gene or another, non-identified gene [4]. Interestingly, mutations in WT1 and LAMB2 genes have been both associated not only to isolated CNS [4,8] but also to more complex entities including developmental disorders [9] and distinct ocular anomalies (Pierson syndrome) [10]. Lastly, mutations in two additional genes were identified in some cases of nonsyndromic CNS: PLCE1 gene involved in the RAS/MAPK signalling pathway and COQ2 gene involved in the coenzyme Q10 biosynthetic [11,12]. This paper is an Editorial Comment that reports on a cohort of 67 patients (from 62 different families belonging to 21 different ethnicities) with CNS [13]. In 36 families, the two disease-causing changes were identified in the NPHS1 gene [13], confirming a former study from the same group showing that one-half of CNS among a large multi-ethnic cohort of patients is caused by recessive mutations in this gene [4]. In nine other affected children, a single mutation in the NPHS1 gene was identified [13]. Interestingly, despite the wide variety of ethnic background, 26 families showed homozygous disease-causing mutation (26 of 36, 72%), mostly explained by a high degree of consanguinity as observed in previous studies on NPHS1 mutational spectrum [14,15]. Overall 37 different NPHS1 mutations, 19 of which are novel, were identified in 44 unrelated patients [13]. Most novel mutations found in this cohort were missense (11 of 19, 58%) but also included some splice-site [4] and nonsense mutations [3] and one small deletion. It is worthy to note that two novel homozygous recessive NPHS1 mutations (p.L587R and p.S910P) were identified in two siblings and two unrelated children [13]. All four patients had an unusually late onset of nephrotic syndrome ranging from the age of 90 days to the age of 2 years [13]. Nephrin is a 1241-residue transmembrane adhesion protein consisting of eight extracellular Ig-like domains, one fibronectin type III motif and a cytosolic C-terminal tail [16]. Nephrin directly participates in the structural basis of the slit diaphragm by its ability to homoor heterodimerize [17]. Available in vitro studies have showed that most NPHS1 missense mutations lead to abnormal retention of nephrin in the endoplasmic reticulum, and therefore it fails to traffic out to the cell surface [18]. These functional data suggested then that the majority of NPHS1 mutations (i.e truncated and missense) result in a loss of function of nephrin which might then explain severe and early-onset phenotype. Strikingly, mutations in the NPHS1 gene were recent-