J Med Genet 49:533-538 doi:10.1136/jmedgenet-2012-101039
  • New disease loci
  • Original article

PAPSS2 mutations cause autosomal recessive brachyolmia

  1. Shiro Ikegawa3
  1. 1Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  2. 2Department of Pediatric Genetics, Marmara University Pendik Hospital, Istanbul, Turkey
  3. 3Laboratory for Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, Tokyo, Japan
  4. 4Department of Pediatrics and Pediatric Endocrinology, Medeniyet University Goztepe Hospital, Istanbul, Turkey
  5. 5Department of Pediatrics, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan
  6. 6Department of Orthopaedic Surgery, Fukuoka Children's Hospital, Fukuoka, Japan
  7. 7Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Korea
  8. 8Department of Radiology, Ajou University Hospital, Suwon, Korea
  9. 9Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
  10. 10Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan
  11. 11Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Futyu, Japan
  1. Correspondence to Noriko Miyake, Department of Human Genetics, Yokohama City University Graduate School of Medicine, 3-9, Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan; nmiyake{at} or Shiro Ikegawa, Laboratory of Bone and Joint Diseases, Center for Genomic Medicine, RIKEN 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; sikegawa{at}
  1. NM, NHE and AI contributed equally to this work.

  2. Contributors NM performed the exome experiments, analysed the data, wrote the paper, and is guarantor. NE and PI collected family samples and evaluated their phenotypes. AI performed the sequence experiments, analysed the data, and wrote the paper. JD performed the experiments. NoM, KM, TC, OK, and TN collected samples and evaluated their clinical and radiographic phenotypes. TH and GN analysed the clinical data. HO collected and controlled the experimental samples. NaM performed the experiments and analysed the data. SI analysed the data, wrote the paper, and is also guarantor. All authors have critically revised the paper.

  • Received 8 May 2012
  • Revised 8 June 2012
  • Accepted 10 June 2012
  • Published Online First 11 July 2012


Background Brachyolmia is a heterogeneous group of skeletal dysplasias that primarily affects the spine. Clinical and genetic heterogeneity have been reported; at least three types of brachyolmia are known. TRPV4 mutations have been identified in an autosomal dominant form of brachyolmia; however, disease genes for autosomal recessive (AR) forms remain totally unknown. We conducted a study on a Turkish family with an AR brachyolmia, with the aim of identifying a disease gene for AR brachyolmia.

Methods and results We examined three affected individuals of the family using exon capture followed by next generation sequencing and identified its disease gene, PAPSS2 (phosphoadenosine-phosphosulfate synthetase 2). The patients had a homozygous loss of function mutation, c.337_338insG (p.A113GfsX18). We further examined three patients with similar brachyolmia phenotypes (two Japanese and a Korean) and also identified loss of function mutations in PAPSS2; one patient was homozygous for IVS3+2delT, and the other two were compound heterozygotes for c.616-634del19 (p.V206SfsX9) and c.1309-1310delAG (p.R437GfsX19), and c.480_481insCGTA (p.K161RfsX6) and c.661delA (p.I221SfsX40), respectively. The six patients had short-trunk short stature that became conspicuous during childhood with normal intelligence and facies. Their radiographic features included rectangular vertebral bodies with irregular endplates and narrow intervertebral discs, precocious calcification of rib cartilages, short femoral neck, and mildly shortened metacarpals. Spinal changes were very similar among the six patients; however, epiphyseal and metaphyseal changes of the tubular bones were variable.

Conclusions We identified PAPSS2 as the disease gene for an AR brachyolmia. PAPSS2 mutations have produced a skeletal dysplasia family, with a gradation of phenotypes ranging from brachyolmia to spondylo-epi-metaphyseal dysplasia.


  • Funding This study is supported by research grants from the Ministry of Health, Labour and Welfare (23300101: S Ikegawa and N Matsumoto; 23300102: T Hasegawa; 23300201: S Ikegawa), by a Grant-in-Aid for Young Scientists from the Japan Society for the Promotion of Science (N Miyake), and by Research on intractable diseases, Health and Labour Sciences Research Grants, H23-Nanchi-Ippan-123 (S Ikegawa).

  • Patient consent Obtained.

  • Ethics approval This study was performed under the approval of the ethical committee of RIKEN, Yokohama City University, and participating institutions.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Additional unpublished data on mutation examination are available on request to researchers.