Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies.
Noonan syndrome is an autosomal dominant disease characterized by dysmorphic features, webbed neck, cardiac anomalies, short stature and cryptorchidism. It shows phenotypic overlap with Costello syndrome and cardio-facio-cutaneous (CFC) syndrome. Noonan syndrome and related disorders are caused by germline mutations in genes encoding molecules in the RAS/MAPK pathway. Recently, a gain-of-function mutation in SHOC2, p.S2G, has been identified as causative for a type of Noonan-like syndrome characterized by the presence of loose anagen hair. In order to understand the contribution of SHOC2 mutations to the clinical manifestations of Noonan syndrome and related disorders, we analyzed SHOC2 in 92 patients with Noonan syndrome and related disorders who did not exhibit PTPN11, KRAS, HRAS, BRAF, MAP2K1/2, SOS1 or RAF1 mutations. We found the previously identified p.S2G mutation in eight of our patients. We developed a rapid detection system to identify the p.S2G mutation using melting curve analysis, which will be a useful tool to screen for the apparently common mutation. All the patients with the p.S2G mutation showed short stature, sparse hair and atopic skin. Six of the mutation-positive patients showed severe mental retardation and easily pluckable hair, and one showed leukocytosis. No SHOC2 mutations were identified in leukemia cells from 82 leukemia patients. These results suggest that clinical manifestations in SHOC2 mutation-positive patients partially overlap with those in patients with typical Noonan or CFC syndrome and show that easily pluckable/loose anagen hair is distinctive in SHOC2 mutation-positive patients.
Komatsuzaki
Shoko
S
Department of Medical Genetics, Tohoku University School of Medicine, 1-1 Seiryo-machi, Sendai, Miyagi, Japan.
Aoki
Yoko
Y
Niihori
Tetsuya
T
Okamoto
Nobuhiko
N
Hennekam
Raoul C M
RC
Hopman
Saskia
S
Ohashi
Hirofumi
H
Mizuno
Seiji
S
Watanabe
Yoriko
Y
Kamasaki
Hotaka
H
Kondo
Ikuko
I
Moriyama
Nobuko
N
Kurosawa
Kenji
K
Kawame
Hiroshi
H
Okuyama
Ryuhei
R
Imaizumi
Masue
M
Rikiishi
Takeshi
T
Tsuchiya
Shigeru
S
Kure
Shigeo
S
Matsubara
Yoichi
Y
D000293:Adolescent; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D015870:Gene Expression; D019337:Hematologic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation; D009634:Noonan Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics; D055815:Young Adult
D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C112913:SHOC2 protein, human