title: Identification and Functional Characterization of Two Novel Nonsense Mutations in the β-Subunit of INSR That Cause Severe Insulin Resistance Syndrome.
abstract: OBJECTIVE
  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 β-subunit of INSR: p.Arg1066* and p.Gln1232*. Western blot analysis of skin fibroblasts revealed a comparable expression of the α-subunit of INSR in mutant and control samples, but reduced levels of mature INSR β-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 β-subunit, which was most likely due to impaired proreceptor processing.
authors.affiliation: Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Minji
authors.initials: M
authors.lastname: Kang
authors.forename: Ja Hye
authors.initials: JH
authors.lastname: Kim
authors.forename: Jahyang
authors.initials: J
authors.lastname: Cho
authors.forename: Gu-Hwan
authors.initials: GH
authors.lastname: Kim
authors.forename: Han-Wook
authors.initials: HW
authors.lastname: Yoo
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D015703:Antigens, CD / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D018389:Codon, Nonsense; D056731:Donohue Syndrome / Q000235:genetics; D017809:Fatal Outcome; D005347:Fibroblasts / Q000737:chemistry; D006801:Humans; D007231:Infant, Newborn; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D011972:Receptor, Insulin / Q000235:genetics*; D013577:Syndrome
chemical_list: D015703:Antigens, CD; D018389:Codon, Nonsense; C435941:INSR protein, human; D011972:Receptor, Insulin