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

Katta M. Girisha, Leonie von Elsner, Kausthubham Neethukrishna, Mamta Muranjan, Anju Shukla, Gandham Sri Lakshmi Bhavani, Gen Nishimura, Kerstin Kutsche, Geert Mortier

Research output: Contribution to journalArticle

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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.

Original languageEnglish
JournalHuman Mutation
DOIs
Publication statusPublished - 01-01-2019

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Epiphyses
Exome
Ethanolamine
Mitochondrial Membranes
Cell Survival
Apoptosis
Caspase 7
Hallux Valgus
Consanguinity
Chromosomes, Human, Pair 22
Decarboxylation
Staurosporine
Phosphatidylserines
Caspase 3
Fibroblasts
phosphatidylethanolamine
benzyloxycarbonylleucyl-leucyl-leucine aldehyde
Therapeutics

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Girisha, Katta M. ; von Elsner, Leonie ; Neethukrishna, Kausthubham ; Muranjan, Mamta ; Shukla, Anju ; Bhavani, Gandham Sri Lakshmi ; Nishimura, Gen ; Kutsche, Kerstin ; Mortier, Geert. / The homozygous variant c.797G>A/p.(Cys266Tyr) in PISD is associated with a Spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function. In: Human Mutation. 2019.
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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.",
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The homozygous variant c.797G>A/p.(Cys266Tyr) in PISD is associated with a Spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function. / Girisha, Katta M.; von Elsner, Leonie; Neethukrishna, Kausthubham; Muranjan, Mamta; Shukla, Anju; Bhavani, Gandham Sri Lakshmi; Nishimura, Gen; Kutsche, Kerstin; Mortier, Geert.

In: Human Mutation, 01.01.2019.

Research output: Contribution to journalArticle

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AU - Girisha, Katta M.

AU - von Elsner, Leonie

AU - Neethukrishna, Kausthubham

AU - Muranjan, Mamta

AU - Shukla, Anju

AU - Bhavani, Gandham Sri Lakshmi

AU - Nishimura, Gen

AU - Kutsche, Kerstin

AU - Mortier, Geert

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