title: Mutations in NOTCH2 in patients with Hajdu-Cheney syndrome.
abstract: The Hajdu-Cheney syndrome is a very rare disease that affects several organ system, leading to severe osteoporosis and other abnormalities. We describe clinical and genetic findings of nine patients with this disease.
  
  
  BACKGROUND
  The Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant disorder characterized by severe osteoporosis, acroosteolysis of the distal phalanges, renal cysts, and other abnormalities. Recently, heterozygous mutations in NOTCH2 were identified as the cause of HCS.
  
  
  METHODS
  Nine patients with typical presentations of HCS took part in this study: five affected patients from two small families and four sporadic cases. Peripheral blood DNA was obtained and exome sequencing performed in one affected individual per family and in all four sporadic cases. Sanger sequencing confirmed mutations in all patients.
  
  
  RESULTS
  One of the identified mutations was introduced in a plasmid encoding NOTCH2. Wild-type and mutant NOTCH2 were transiently expressed in HEK293 cells to assess intracellular localization after ligand activation. Deleterious heterozygous mutations in the last NOTCH2 exon were identified in all patients; five of the six mutations were novel.
  
  
  CONCLUSIONS
  Consistent with previous reports, all mutations are predicted to result in a loss of the proline/glutamic acid/serine/threonine sequence, which harbors signals for degradation, therefore suggesting activating mutations. One of the six mutations furthermore predicted disruption of the second nuclear localization signal of NOTCH2, but the mutant revealed normal nuclear localization after transfection, which is consistent with the proposed gain-of-function mechanism as the cause of this autosomal dominant disease. Our findings confirm that heterozygous NOTCH2 mutations are the cause of HCS and expand the mutational spectrum of this disorder.
authors: Endocrine Unit, Thier 10, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
authors: W
authors: W
authors: Zhao
authors: E
authors: E
authors: Petit
authors: R I
authors: RI
authors: Gafni
authors: M T
authors: MT
authors: Collins
authors: P G
authors: PG
authors: Robey
authors: M
authors: M
authors: Seton
authors: K K
authors: KK
authors: Miller
authors: M
authors: M
authors: Mannstadt
mesh_terms: D000293:Adolescent; D000328:Adult; D059472:Exome / Q000235:genetics; D005260:Female; D050278:Finger Phalanges / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000473:pathology; D031845:Hajdu-Cheney Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010024:Osteoporosis / Q000235:genetics; D010375:Pedigree; D011859:Radiography; D051883:Receptor, Notch2 / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D055815:Young Adult
chemical_list: C497764:NOTCH2 protein, human; D051883:Receptor, Notch2
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