title: Exome sequencing reveals a novel PTHLH mutation in a Chinese pedigree with brachydactyly type E and short stature.
abstract: Brachydactyly includes shortening of digits due to abnormal development of phalanges, metacarpals, or both. It can occur either as an isolated malformation or with other anomalies as part of many congenital syndromes. It is included as one of the dysostosis groups affecting the limbs in the nosology and classification of genetic skeletal disorders. However, brachydactyly usually shows a high degree of phenotypic variability. In this study, we successfully identified a novel heterozygous mutation of the parathyroid hormone-like hormone (PTHLH) gene by exome sequencing in a Chinese pedigree with brachydactyly and short stature. The PTHLH gene encodes a parathyroid hormone-related protein (PTHrP) that is involved in the regulation of endochondral bone development, and mutations in this gene cause the type E form of brachydactyly. The mutation p.L15R occurs at a hydrophobic core region of the signal peptide, suggesting that this variation probably changes the signal peptide cleavage site at the in silico prediction. Further in vitro functional analysis showed that this mutation can lead to the retention of an N-terminal signal peptide fragment after the nascent proteins are translated.
authors: State Key laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors: Jian
authors: J
authors: Wang
authors: Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors: Zhigang
authors: Z
authors: Wang
authors: Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors: Yu
authors: Y
authors: An
authors: Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors: Chunxing
authors: C
authors: Wu
authors: Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors: Yunlan
authors: Y
authors: Xu
authors: Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors: Qihua
authors: Q
authors: Fu
authors: Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China; Boston Children's Hospital, Boston, MA, USA.
authors: Yiping
authors: Y
authors: Shen
authors: State Key laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: qhzhang@wayenbio.com.
authors: Qinghua
authors: Q
authors: Zhang
mesh_terms: D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics*; D001827:Body Height / Q000235:genetics*; D059327:Brachydactyly / Q000175:diagnosis / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics*; D010375:Pedigree; D020539:Sequence Analysis, Protein / Q000379:methods
chemical_list: C470121:PTHLH protein, human; D044162:Parathyroid Hormone-Related Protein
keywords: Brachydactyly; Exome sequencing; Mutation; PTHLH gene; Signal peptide