Identification and Functional Characterization of Two Novel Nonsense Mutations in the beta- Subunit of INSR That Cause Severe Insulin Resistance Syndrome

摘要

Background/Aims: Donohue syndrome is an extremely rare autosomal recessive disorder caused by mutations in INSR. This study describes the clinical course of a patient with Donohue syndrome, and we also evaluated the molecular and functional characteristics of 2 novel INSR mutations. Methods: Our patient was a male newborn with acanthosis nigricans, lack of subcutaneous fat, hirsutism, thick lips, and high serum insulin levels, all of which are characteristic of Donohue syndrome. INSR mutation analysis was performed, and Western blot analysis was used to verify the effects of the novel mutations on INSR protein expression. Results: Direct INSR sequencing identified the following 2 novel compound heterozygous mutations in the beta-subunit of INSR : p.Arg1066* and p.Gln1232*. Western blot analysis of skin fibroblasts revealed a comparable expression of the alpha-subunit of INSR in mutant and control samples, but reduced levels of mature INSR beta-subunit protein were found in mutant INSR-expressing cells in comparison to the controls. Conclusions: This study describes the clinical course of a male patient with Donohue syndrome and the molecular characteristics of 2 novel compound heterozygous mutations in INSR. These novel nonsense mutations are associated with reduced expression of the mature INSR beta-subunit, which was most likely due to impaired proreceptor processing. (C) 2015 S. Karger AG, Basel