Stop codon at arginine 586 is the prevalent nephronopthisis type 1 mutation in Italy

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Abstract
Nephronophthisis (NPHP) is an autosomal recessive disease with prevalent renal manifestations, characterized by occasional cysts in medulla and severe tubulo-interstitial fibrosis, evolving to end-stage renal failure [1]. It represents the most frequent cause of uraemia in children, with major clinical, physiological and social consequences including high costs for substitutive approaches and renal transplant. NPHP is a clinical and genetic heterogeneous disease with at least five genes (NPHP1–5) identified and variable extra-renal manifestations [2–6 ]. Retinal dysfunction constituting Senior Loken syndrome (SLS1–5) is the most common association [1]. Other organ defects identify specific subsets such as liver fibrosis in NPHP3 and situs inversus in NPHP2. NPHP1 [OMIM #256100] represents the most frequent variant. On a molecular basis, the large majority of patients with NPHP1 present a large homozygous deletion [7] at 2q13 [NPHP1-del] that includes nephrocystin, the NPHP1 gene [2,8]. Patients with NPHP1 gene mutations are rare. A revision of the literature reveals only one case with compound heterozygous mutation, while less uncommon is the combination of [NPHP1-del] with a point mutation of NPHP1 ‘in trans’ [2,8–13 ], which has been reported in 11 cases (Table 1). Hildebrandt et al. [12] calculated the probability of compound heterozygous NPHP1 mutation in 1 out of 109. Based on these frequencies, molecular analysis of NPHP1 is indicated only in patients with heterozygous [NPHP1-del] [12].