title: Three novel IGSF1 mutations in four Japanese patients with X-linked congenital central hypothyroidism.
abstract: BACKGROUND
  Congenital central hypothyroidism (C-CH) is a rare disease. We investigated the molecular basis of unexplained C-CH in 4 Japanese boys.
  
  
  METHODS
  C-CH was diagnosed by low free T4 and/or T3 and low basal TSH concentrations. We used whole-exome sequencing of one patient with C-CH to identify potential disease-causing mutations. Thereafter, PCR direct sequencing was performed to Identify genetic defects underlying C-CH in 3 more patients. We then assessed the effects of mutations identified in the Ig superfamily, member 1 (IGSF1), gene on protein expression and membrane trafficking.
  
  
  RESULTS
  All patients had congenital hypothyroidism, and 2 had definitive prolactin deficiency. Two patients were detected by neonatal screening. The other patients were diagnosed by short stature and failure to thrive. We identified a novel nonsense variant in IGSF1 by whole-exome sequencing in patient 1, which was confirmed by PCR direct sequencing (p.R1189X). PCR direct sequencing identified the identical nonsense mutation in patient 2. Patients 3 and 4 harbored distinct missense (p.V1082E) or nonsense (p.Q645X) mutations in IGSF1. The mothers of patients 1, 3, and 4 were heterozygous for these mutations. The R1189X mutant, which lacks the transmembrane domain, failed to traffic to the plasma membrane. V1082E could be observed at the cell surface, but at greatly diminished levels relative to the wild-type form of the protein. The severely truncated Q645X mutant could not be detected by Western blot.
  
  
  CONCLUSIONS
  Our findings provide additional genetic evidence that loss-of-function mutations in IGSF1 cause an X-linked form of C-CH and variable prolactin deficiency.
authors: MD, Department of Pediatrics, Hokkaido University School of Medicine, North 15 West 7, Kitaku, Sapporo, Japan 060-8635. akieda@med.hokudai.ac.jp.
authors: Akie
authors: A
authors: Nakamura
authors: Beata
authors: B
authors: Bak
authors: Tanya L R
authors: TL
authors: Silander
authors: Jessica
authors: J
authors: Lam
authors: Tomoyuki
authors: T
authors: Hotsubo
authors: Toru
authors: T
authors: Yorifuji
authors: Katsura
authors: K
authors: Ishizu
authors: Daniel J
authors: DJ
authors: Bernard
authors: Toshihiro
authors: T
authors: Tajima
mesh_terms: D002675:Child, Preschool; D003409:Congenital Hypothyroidism / Q000097:blood / Q000235:genetics*; D050172:Genes, X-Linked; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D011388:Prolactin / Q000097:blood / Q000172:deficiency; D013972:Thyrotropin / Q000097:blood
chemical_list: C112314:IGSF1 protein, human; D007136:Immunoglobulins; D008565:Membrane Proteins; D011388:Prolactin; D013972:Thyrotropin