Novel biallelic PISD missense variants cause spondyloepimetaphyseal dysplasia with disproportionate short stature and fragmented mitochondrial morphology

Line Aagaard Nolting*, Tess Holling, Gen Nishimura, Jakob Ek, Mads Bak, Merete Ljungberg, Kerstin Kutsche, Hanne Hove

*Corresponding author for this work
1 Citation (Scopus)

Abstract

Biallelic variants in PISD cause a phenotypic spectrum ranging from short stature with spondyloepimetaphyseal dysplasia (SEMD) to a multisystem disorder affecting eyes, ears, bones, and brain. PISD encodes the mitochondrial-localized enzyme phosphatidylserine decarboxylase. The PISD precursor is self-cleaved to generate a heteromeric mature enzyme that converts phosphatidylserine to the phospholipid phosphatidylethanolamine. We describe a 17-year-old male patient, born to unrelated healthy parents, with disproportionate short stature and SEMD, featuring platyspondyly, prominent epiphyses, and metaphyseal dysplasia. Trio genome sequencing revealed compound heterozygous PISD variants c.569C>T; p.(Ser190Leu) and c.799C>T; p.(His267Tyr) in the patient. Investigation of fibroblasts showed similar levels of the PISD precursor protein in both patient and control cells. However, patient cells had a significantly higher proportion of fragmented mitochondria compared to control cells cultured under basal condition and after treatment with 2-deoxyglucose that represses glycolysis and stimulates respiration. Structural data from the PISD orthologue in Escherichia coli suggest that the amino acid substitutions Ser190Leu and His267Tyr likely impair PISD's autoprocessing activity and/or phosphatidylethanolamine biosynthesis. Based on the data, we propose that the novel PISD p.(Ser190Leu) and p.(His267Tyr) variants likely act as hypomorphs and underlie the pure skeletal phenotype in the patient.

Original languageEnglish
JournalClinical Genetics
Volume106
Issue number3
Pages (from-to)360-366
Number of pages7
ISSN0009-9163
DOIs
Publication statusPublished - 2024

Keywords

  • Adolescent
  • Alleles
  • Carboxy-Lyases/genetics
  • Dwarfism/genetics
  • Humans
  • Male
  • Mitochondria/genetics
  • Mutation, Missense/genetics
  • Osteochondrodysplasias/genetics
  • Phenotype
  • phosphatidylserine decarboxylase
  • spondyloepimetaphyseal dysplasia
  • Liberfarb syndrome
  • mitochondrial dysfunction
  • PISD
  • SEMD

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