1. Academic Validation
  2. The homozygous variant c.797G>A/p.(Cys266Tyr) in PISD is associated with a Spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function

The homozygous variant c.797G>A/p.(Cys266Tyr) in PISD is associated with a Spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function

  • Hum Mutat. 2019 Mar;40(3):299-309. doi: 10.1002/humu.23693.
Katta M Girisha 1 Leonie von Elsner 2 Kausthubham Neethukrishna 1 Mamta Muranjan 3 4 Anju Shukla 1 Gandham SriLakshmi Bhavani 1 Gen Nishimura 5 Kerstin Kutsche 2 Geert Mortier 6
Affiliations

Affiliations

  • 1 Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India.
  • 2 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 3 Department of Clinical Genetics, Seth GS Medical College and KEM Hospital, Mumbai, India.
  • 4 Consultant in Clinical Genetics, P.D. Hinduja National Hospital & MRC, Mumbai, India.
  • 5 Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Fuchu, Japan.
  • 6 Centre of Medical Genetics, University of Antwerp & University Hospital Antwerp, Antwerp, Belgium.
Abstract

Spondyloepimetaphyseal dysplasias (SEMD) are a group of genetically heterogeneous skeletal disorders characterized by abnormal vertebral bodies and epimetaphyseal abnormalities. We investigated two families with a new SEMD type with one proband each. They showed mild facial dysmorphism, flat vertebral bodies (platyspondyly), large epiphyses, metaphyseal dysplasia, and hallux valgus as common clinical features. By trio-exome Sequencing, the homozygous missense variant c.797G>A/p.(Cys266Tyr) in PISD was found in both affected individuals. Based on exome data analyses for homozygous regions, the two patients shared a single homozygous block on chromosome 22 including PISD, indicating their remote consanguinity. PISD encodes phosphatidylserine (PS) decarboxylase that is localized in the inner mitochondrial membrane and catalyzes the decarboxylation of PS to phosphatidylethanolamine (PE) in mammalian cells. PE occurs at high abundance in mitochondrial membranes. Patient-derived fibroblasts showed fragmented mitochondrial morphology. Treatment of patient cells with MG-132 or staurosporine to induce activation of the intrinsic Apoptosis pathway revealed significantly decreased cell viability with increased Caspase-3 and caspase-7 activation. Remarkably, ethanolamine (Etn) supplementation largely restored cell viability and enhanced Apoptosis in MG-132-stressed patient cells. Our data demonstrate that the biallelic hypomorphic PISD variant p.(Cys266Tyr) is associated with a novel SEMD form, which may be treatable with Etn administration.

Keywords

hypomorphic mutation; mitochondrial dysfunction; phosphatidylethanolamine; phosphatidylserine decarboxylase; spondyloepimetaphyseal dysplasia.

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