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Original research
Novel form of rhizomelic skeletal dysplasia associated with a homozygous variant in GNPNAT1
  1. Noor Ul Ain1,2,
  2. Marta Baroncelli3,
  3. Alice Costantini2,
  4. Tayyaba Ishaq1,
  5. Fulya Taylan2,
  6. Ola Nilsson3,4,
  7. Outi Mäkitie2,5,6,
  8. Sadaf Naz1
  1. 1School of Biological Sciences, University of the Punjab, Lahore, Pakistan
  2. 2Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  3. 3Center for Molecular Medicine and Pediatric Endocrinology Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
  4. 4School of Medical Sciences, Örebro University and Örebro University Hospital, Örebro, Sweden
  5. 5Children’s Hospital, University of Helsinki, Helsinki, Finland
  6. 6Folkhälsan Institute of Genetics, Helsinki, Finland
  1. Correspondence to Dr Sadaf Naz, School of Biological Sciences, University of the Punjab, Lahore 54590, Pakistan;{at}; Dr Outi Mäkitie; outi.makitie{at}


Background Studies exploring molecular mechanisms underlying congenital skeletal disorders have revealed novel regulators of skeletal homeostasis and shown protein glycosylation to play an important role.

Objective To identify the genetic cause of rhizomelic skeletal dysplasia in a consanguineous Pakistani family.

Methods Clinical investigations were carried out for four affected individuals in the recruited family. Whole genome sequencing (WGS) was completed using DNA from two affected and two unaffected individuals from the family. Sequencing data were processed, filtered and analysed. In silico analyses were performed to predict the effects of the candidate variant on the protein structure and function. Small interfering RNAs (siRNAs) were used to study the effect of Gnpnat1 gene knockdown in primary rat chondrocytes.

Results The patients presented with short stature due to extreme shortening of the proximal segments of the limbs. Radiographs of one individual showed hip dysplasia and severe platyspondyly. WGS data analyses identified a homozygous missense variant c.226G>A; p.(Glu76Lys) in GNPNAT1, segregating with the disease. Glucosamine 6-phosphate N-acetyltransferase, encoded by the highly conserved gene GNPNAT1, is one of the enzymes required for synthesis of uridine diphosphate N-acetylglucosamine, which participates in protein glycosylation. Knockdown of Gnpnat1 by siRNAs decreased cellular proliferation and expression of chondrocyte differentiation markers collagen type 2 and alkaline phosphatase, indicating that Gnpnat1 is important for growth plate chondrocyte proliferation and differentiation.

Conclusions This study describes a novel severe skeletal dysplasia associated with a biallelic, variant in GNPNAT1. Our data suggest that GNPNAT1 is important for growth plate chondrogenesis.

  • genetics
  • molecular genetics
  • cell biology
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  • OM and SN contributed equally.

  • Contributors SN and OM designed and supervised the study. TI and NUA collected the family samples and arranged clinical testing. NUA analysed genome sequencing data and performed Sanger sequencing. AC and FT analysed data. MB and NUA performed and analysed knockdown experiments. ON supervised knockdown experiments. OM and ON reviewed clinical data. NUA, OM and SN wrote the manuscript. All authors reviewed and approved the manuscript.

  • Funding NUA was supported by International Research Support Program (IRSP) provided by HEC, Pakistan. MB was supported by a scholarship from The Foundation Blanceflor Boncompagni Ludovisi, née Bild. ON and MB were supported by grants from the Swedish Research Council (project K2015-54X-22 736-01-4 and 2015-02227), the Swedish Governmental Agency for Innovation Systems (Vinnova) (2014-01438), Marianne and Marcus Wallenberg Foundation, IngaBritt och Arne Lundbergs forskningsstiftelse, Byggmästare Olle Engkvist Stiftelse, Nyckelfonden, Stiftelsen Frimurare Barnhuset i Stockholm, the Stockholm County Council, Karolinska Institutet, Stockholm, Sweden, and Örebro University, Örebro, Sweden. Research of OM was funded by Swedish Research Council, Academy of Finland, Sigrid Jusélius Foundation and Novo Nordisk Foundation grant and that of SN was supported by Koshish foundation USA.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval This study was approved by the Institutional Review Board of School of Biological Sciences, University of the Punjab, Lahore, Pakistan (ethics approval SBS11-1 by IRB no. 00005281). Written informed consents were obtained from all participants. The animal protocol and all procedures were approved by the regional animal ethics committee in Stockholm, Sweden.

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

  • Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplementary information. Data can be available on request from the corresponding authors. The accession number for the variant identified in present study is LOVD:0000645198.

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