Mutationsanalsyen in BBS1 und BBS10 bei Patienten mit dem Bardet-Biedl-Syndrom

The autosomal recessively inherited Bardet-Biedl syndrome (BBS, OMIM 209900) is a disorder affecting primary cilia and microtubule-based structures arising from the basal body. These cell structures are involved as mechanosensors in kidney epithelium, photoreceptor cells of the retina and in the developmental phenomenon of planar cell polarity. The syndrome is phenotypically characterized by postaxial polydactyly, retinopathy, obesity, hypogonadism in males, renal dysfunction and variable mental deficiency. Over the past years it has become obvious that BBS is genetically heterogeneous with several genes (BBS1-BBS12) involved. Molecular analyses have shown that some individuals need mutations in more than one BBS locus for clinical manifestation. Therefore BBS is currently regarded as a disorder with digenic or even oligogenic inheritance. Most mutations are private mutations in the respective individual and his family. Uptil now only two mutations occur more frequently and are present in different populations. In the European population the BBS1 mutation p.Met390Arg is observed in about 18% of individuals with BBS, whereas it is infrequent in the Turkish population. A second major locus is BBS10 in which the mutation p.Cys91LeufsX5 was found in 13% of individuals in different ethnicities. We screened a sample of 76 BBS patients for the BBS1 mutation p.Met390Arg (c.1169T>G) and for the BBS10 mutation p.Cys91LeufsX5 (c.270_271insT). The mutation p.Met390Arg was found in 15% of German but not in any Turkish patients. In addition, we detected in BBS1 five unique mutations in different families: a 50bp insertion in exon 12 (p.Cys377TrpfsX19) , a deletion of exons 12+13 (c.Ex12_Ex13del) , and three point mutations (c.1318C>T, p.Arg440X; c.1339G>A, p.Ala447Thr; c.1660A>T, p.Ser554Cys). The mutation p.Cys91LeufsX5 was found in 28% of German and in 8% of Turkish patients. Additionally we observed in BBS10 a combined 1 bp insertion and point mutation: c.[253_254insA, 254C>G], p.Thr85LysfsX11. In summary, the mutations p.Met390Arg and p.Cys91LeufsX5 were detected in 43% of German patients. Therefore, this limited and low cost molecular test is helpful to support the clinical diagnosis of BBS in our population. The variant p.Cys91LeufsX5 is the most prevalent mutation in German BBS patients and outnumbers p.Met390Arg threefold. In Addition there could not be found any prove for the loci BBS1, BBS6 and BBS10 to be involved in digenic or oligogenic inheritance.