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Biallelic TMEM251 variants in patients with severe skeletal dysplasia and extreme short stature
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  • Noor Ain,
  • Niaz Muhammad,
  • Mehdi Dianatpour,
  • Marta Baroncelli,
  • Muddassar Iqbal,
  • Mohammad A. Farazifard,
  • Ihtisham Bukhari,
  • Sufian Ahmed,
  • Massoumeh Hajipour ,
  • Zahra Tabatabaie,
  • Hamidreza Foroutan ,
  • Ola Nilsson,
  • Mohammad Ali Faghihi,
  • Outi Makitie,
  • Sadaf Naz
Noor Ain
University of the Punjab Quaid-i-Azam Campus
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Niaz Muhammad
University of the Punjab Quaid-i-Azam Campus
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Mehdi Dianatpour
Shiraz University of Medical Sciences
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Marta Baroncelli
Karolinska Institute
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Muddassar Iqbal
University of the Punjab
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Mohammad A. Farazifard
Shiraz University of Medical Sciences
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Ihtisham Bukhari
University of the Punjab
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Sufian Ahmed
University of the Punjab Quaid-i-Azam Campus
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Massoumeh Hajipour
Persian BayanGene Research and Training Center
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Zahra Tabatabaie
Persian BayanGene Research and Training Center
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Hamidreza Foroutan
Persian BayanGene Research and Training Center
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Ola Nilsson
Karolinska Institute
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Mohammad Ali Faghihi
Persian BayanGene Research and Training Center
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Outi Makitie
Karolinska Institute
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Sadaf Naz
University of the Punjab
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Abstract

Skeletal dysplasias are a heterogeneous group of disorders ranging from mild to lethal skeletal defects. We investigated two unrelated families with individuals presenting with a severe skeletal disorder. In family NMD02, affected individuals had a dysostosis multiplex-like skeletal dysplasia and severe short stature (<-8.5 SD). They manifested increasing coarse facial features, protruding abdomens and progressive skeletal changes, reminiscent of mucopolysaccharidosis. The patients gradually lost mobility and the two oldest affected individuals died in their twenties. The affected child in family ID01 had coarse facial features and severe skeletal dysplasia with clinical features similar to mucopolysaccharidosis. She had short stature, craniosynostosis, kyphoscoliosis and hip-joint subluxation. She died at the age of 5 years. Whole-exome sequencing identified two homozygous variants c.133C>T; p.(Arg45Trp) and c.215dupA; p.(Tyr72Ter) respectively, in the two families, affecting an evolutionary conserved gene TMEM251. Immunofluorescence and confocal studies on Human Osteosarcoma cells indicated that TMEM251 localized to the Golgi complex and plasma membrane. However, p.Arg45Trp mutant TMEM251 protein was targeted less efficiently to the membranes and the localization was punctate. Tmem251 knockdown by siRNA induced dedifferentiation of rat primary chondrocytes. Our work implicates TMEM251 in the pathogenesis of a novel disorder and suggests its potential function in chondrocyte differentiation.

Peer review status:IN REVISION

04 Jun 2020Submitted to Human Mutation
10 Jun 2020Assigned to Editor
10 Jun 2020Submission Checks Completed
14 Jun 2020Reviewer(s) Assigned
21 Jul 2020Review(s) Completed, Editorial Evaluation Pending
22 Jul 2020Editorial Decision: Revise Major