Screening the 3 ' region of the polycystic kidney disease 1 (PKD1) gene in41 Bulgarian and Australian kindreds reveals a prevalance of protein truncating mutations

Screening for disease causing mutations in the unique region of the polycys tic kidney disease 1 (PKD1) gene was performed in 41 unrelated individuals with autosomal dominant polycystic kidney disease. Exons 34-41 and 43-46 we re assayed using PCR amplification and SSCP analysis followed by direct seq uencing of amplicons presenting variant SSCP patterns. We have identified s even disease-causing mutations of which five are novel [c.10634-10656del; c .11587delG; IVS37-10C>A; c.11669-11674del; c.13069-13070ins39] and two have been reported previously [Q4010X; Q4041X]. Defects in this part of the gen e thus account for 17% of our group of patients. Five of the seven sequence alterations detected are protein-truncating which is in agree ment with mu tation screening data for this part of the gene by other groups. The two ot her mutations are in-frame deletions or insertions which could destroy impo rtant functional properties of polycystin 1, These findings suggest that th e first step toward cyst formation in PKD1 patients is the loss of one func tional copy of polycystin 1, which indirectly supports the "two-hit" model of cystogenesis where a second somatic mutation inactivating the normal all ele is necessary to occur for develop ment of the disease condition, Hum Mu tat 16:166-174, 2000, (C) 2000 Wiley Liss, Inc.