Title: Das CHARGE-Syndrom – Quantifizierung eines Gonadenmosaiks und Interaktionspartnersuche des CHD7-Gens
Abstract:CHARGE syndrome is an autosomal dominant malformation syndrome. The majority of cases are due to de novo mutations in the CHD7 gene. In only ⅔ of the cases, a mutation in CHD7 gene could be found. In ...CHARGE syndrome is an autosomal dominant malformation syndrome. The majority of cases are due to de novo mutations in the CHD7 gene. In only ⅔ of the cases, a mutation in CHD7 gene could be found. In this study a family with two affected children, both carrying the mutation c.7302dupA in a heterozgous state, is presented. The underlying mutation c.7302dupA could be identified in the sperm of the healthy father. A germline mosaicism could be demonstrated in the father of the affected children. A method of single sperm analysis was established to determine the grade of mosaicism. In this case, the mutation was found in 16 of 59 analyzed sperms. This result leads to a high recurrence risk in further pregnancies. An interaction between CHD7 and CHD8 could be demonstrated in direct yeast-two-hybrid. This result was confirmed by co-localisation of both proteins and by bimolecular fluorescence complementation assay. In further direct yeast-two-hybrid studies, the interacting part of CHD7 was narrowed down to the amio acid area 1950-2172 containing the domains SANT and CR3 with distal and proximal overhangs. There are known CHARGE patients with missense mutations in CHD7 gene in the CHD7 - CHD8 interacting area. One of those missense mutations, namely p.Trp2091Arg, was inserted in CHD7 gene and this lead to a disruption of the interaction in direct yeast-two-hybrid. The missense mutation and its influence on the interaction between CHD7 and CHD8 might be responsible for CHARGE syndrome in this case.Read More