A novel nonsense mutation in NPHS1: is aortic stenosis associated with congenital nephropathy?

Congenital nephrotic syndrome (CNS) is a life-threatening kidney disorder characterized clinically by massive proteinuria and oedema, starts shortly after birth. Mutations in the gene encoding nephrin (NPHS1), one of the essential proteins constituting the glomerular filtration barrier, have been linked to the Finnish-type of CNS. Lately, it was shown that this type is also encountered in many European countries. In the Middle-East, only two reports have shown mutations in NPHS1 to be linked to CNS. Here, we describe the first Lebanese familial Finnish-type nephropathy and unravel a novel mutation in NPHS1, leading to a truncated protein. In addition, we hypothesize that the heterozygous form of the mutation is linked to aortic stenosis, one of the most prevalent congenital heart disease (CHD), since two out of three individuals in the family who are heterozygous for this mutation have aortic stenosis. Taken together with the recent findings in NPHS1 knockout mice which have severe coronary arteries malformations, the results presented here are an eye opener for CNS treating physicians who should have a complete cardiac assessment of their patients. The term ‘nephrotic syndrome’ refers to any condition with excessive proteinuria, hypoalbuminaemia, and oedema (Fuchshuber et al. 1996; Avni et al. 2011). The glomerular capillary wall, which is composed of a basement membrane covered by endothelial cells on the inner part and visceral epithelial cells (podocytes) on the outer part, is responsible for plasma ultrafiltration during urine formation. Dysfunction of the glomerular barrier results in leakage of plasma proteins and the development of nephrotic syndromes (NS). Thus, one would suspect any abnormal expression and/or