Systematic molecular analyses of SHOX in Japanese patients with idiopathic short stature and Leri-Weill dyschondrosteosis.

Abstract

The etiology of idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD) in European patients is known to include SHOX mutations and copy-number variations (CNVs) involving SHOX and/or the highly evolutionarily conserved non-coding DNA elements (CNEs) flanking the gene. However, the frequency and types of SHOX abnormalities in non-European patients and the clinical importance of mutations in the CNEs remains to be clarified. Here, we performed systematic molecular analyses of SHOX for 328 Japanese patients with ISS or LWD. SHOX abnormalities accounted for 3.8% of ISS and 50% of LWD cases. CNVs around SHOX were identified in 16 cases, although the ~47 kb deletion frequently reported in European patients was absent in our cases. Probably damaging mutations and benign/silent substitutions were detected in four cases, respectively. Although CNE-linked substitutions were detected in 15 cases, most of them affected poorly conserved nucleotides and were shared by unaffected individuals. These results suggest that the frequency and mutation spectrum of SHOX abnormalities are comparable between Asian and European patients, with the exception of a European-specific downstream deletion. Furthermore, this study highlights the clinical importance and genetic heterogeneity of the SHOX-flanking CNVs, and indicates a limited clinical significance of point mutations in the CNEs.

• Authors: Hirohito Shima, Toshiaki Tanaka, Tsutomu Kamimaki, Sumito Dateki, Koji Muroya, Reiko Horikawa, Junko Kanno, Masanori Adachi, Yasuhiro Naiki, Hiroyuki Tanaka, Hiroyo Mabe, Hideaki Yagasaki, Shigeo Kure, Yoichi Matsubara, Toshihiro Tajima, Kenichi Kashimada, Tomohiro Ishii, Yumi Asakura, Ikuma Fujiwara, Shun Soneda, Keisuke Nagasaki, Takashi Hamajima, Susumu Kanzaki, Tomoko Jinno, Tsutomu Ogata, Maki Fukami, Japanese SHOX study group
• Journal: Journal of human genetics (J Hum Genet) Vol. 61 Issue 7 Pg. 585-91 (Jul 2016) ISSN: 1435-232X [Electronic] England
• PMID: 26984564 (Publication Type: Journal Article)

Chemical References

• Homeodomain Proteins
• SHOX protein, human
• Short Stature Homeobox Protein

Topics

• Adolescent
• Child
• Child, Preschool
• Cohort Studies
• DNA Copy Number Variations
• Dwarfism (diagnosis, genetics)
• Female
• Genetic Association Studies
• Genetic Heterogeneity
• Genetic Variation
• Growth Disorders (diagnosis, genetics)
• Homeodomain Proteins (genetics)
• Humans
• Infant
• Japan
• Male
• Mutation
• Osteochondrodysplasias (diagnosis, genetics)
• Phenotype
• Sequence Analysis, DNA
• Short Stature Homeobox Protein
• Syndrome