title: Isolated growth hormone deficiency in two siblings because of paternal mosaicism for a mutation in the GH1 gene.
abstract: BACKGROUND
  Mutations in the GH1 gene have been identified in patients with isolated growth hormone deficiency (IGHD). Mutations causing aberrant splicing of exon 3 of GH1 that have been identified in IGHD are inherited in an autosomal dominant manner, whereas other mutations in GH1 that have been identified in IGHD are inherited in an autosomal recessive manner.
  
  
  OBJECTIVE
  Two siblings born from nonconsanguineous healthy parents exhibited IGHD. To elucidate the cause, GH1 in all family members was analysed.
  
  
  RESULTS
  Two novel mutations in GH1, a point mutation in intron 3 and a 16-bp deletion in exon 3, were identified by sequence analyses. The intronic mutation was present in both siblings and was predicted to cause aberrant splicing. The deletion was present in one of the siblings as well as the mother with normal stature and was predicted to cause rapid degradation of mRNA through nonsense-mediated mRNA decay. The point mutation was not identified in the parents' peripheral blood DNA; however, it was detected in the DNA extracted from the father's sperms. As a trace of the mutant allele was detected in the peripheral blood of the father using PCR-RFLP, the mutation is likely to have occurred de novo at an early developmental stage before differentiation of somatic cells and germline cells.
  
  
  CONCLUSIONS
  This is the first report of mosaicism for a mutation in GH1 in a family with IGHD. It is clear that the intronic mutation plays a dominant role in the pathogenesis of IGHD in this family, as one of the siblings who had only the point mutation was affected. On the other hand, the other sibling was a compound heterozygote for the point mutation and the 16-bp deletion and it may be arguable whether IGHD in this patient should be regarded as autosomal dominant or recessive.
authors.affiliation: Department of Pediatrics, Juntendo University Faculty of Medicine, Hongo, Bunkyo-ku, Tokyo. mayukokatoh@gmail.com
authors.forename: Mayuko
authors.initials: M
authors.lastname: Tsubahara
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Niijima
authors.forename: Michiyo
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Kamijo
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Murata
authors.forename: Hidenori
authors.initials: H
authors.lastname: Haruna
authors.forename: Akihisa
authors.initials: A
authors.lastname: Okumura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D001483:Base Sequence; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005220:Fathers; D005260:Female; D019382:Human Growth Hormone / Q000172:deficiency* / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009030:Mosaicism; D009154:Mutation; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D017384:Sequence Deletion; D035781:Siblings
chemical_list: D022821:RNA Splice Sites; D019382:Human Growth Hormone