Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy

Salma Ben-Salem, Sarah M. Robbins, Nara Sobreira, Angeline Lyon, Aisha M. Al-Shamsi, Barira K. Islam, Nadia A. Akawi, Anne John, Pramathan Thachillath, Sania Al Hamed, David Valle, Bassam R. Ali, Lihadh Al-Gazali

Research output: Contribution to journalArticle

Abstract

Background Bone dysplasias are a large group of disorders affecting the growth and structure of the skeletal system. Methods In the present study, we report the clinical and molecular delineation of a new form of syndromic autosomal recessive spondylometaphyseal dysplasia (SMD) in two Emirati first cousins. They displayed postnatal growth deficiency causing profound limb shortening with proximal and distal segments involvement, narrow chest, radiological abnormalities involving the spine, pelvis and metaphyses, corneal clouding and intellectual disability. Whole genome homozygosity mapping localised the genetic cause to 11q12.1-q13.1, a region spanning 19.32 Mb with ∼490 genes. Using whole exome sequencing, we identified four novel homozygous variants within the shared block of homozygosity. Pathogenic variants in genes involved in phospholipid metabolism, such as PLCB4 and PCYT1A, are known to cause bone dysplasia with or without eye anomalies, which led us to select PLCB3 as a strong candidate. This gene encodes phospholipase C β 3, an enzyme that converts phosphatidylinositol 4,5 bisphosphate (PIP 2) to inositol 1,4,5 triphosphate (IP 3) and diacylglycerol. Results The identified variant (c.2632G>T) substitutes a serine for a highly conserved alanine within the Ha2' element of the proximal C-terminal domain. This disrupts binding of the Ha2' element to the catalytic core and destabilises PLCB3. Here we show that this hypomorphic variant leads to elevated levels of PIP 2 in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton. Conclusions Our results connect a homozygous loss of function variant in PLCB3 with a new SMD associated with corneal dystrophy and developmental delay (SMDCD).

Original languageEnglish (US)
Pages (from-to)122-130
Number of pages9
JournalJournal of Medical Genetics
Volume55
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

Phosphatidylinositols
Developmental Bone Disease
Growth Disorders
Genes
Exome
Inositol 1,4,5-Trisphosphate
Chromosome Mapping
Diglycerides
Type C Phospholipases
Pelvis
Actin Cytoskeleton
Intellectual Disability
Alanine
Serine
Actins
Catalytic Domain
Phospholipids
Spine
Thorax
Extremities

Keywords

  • disorganization of actin cytoskeletal network
  • hypomorphic variant
  • pip2 accumulation
  • plcb3
  • spondylometaphyseal dysplasia with corneal dystrophy (smdcd)

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy. / Ben-Salem, Salma; Robbins, Sarah M.; Sobreira, Nara; Lyon, Angeline; Al-Shamsi, Aisha M.; Islam, Barira K.; Akawi, Nadia A.; John, Anne; Thachillath, Pramathan; Al Hamed, Sania; Valle, David; Ali, Bassam R.; Al-Gazali, Lihadh.

In: Journal of Medical Genetics, Vol. 55, No. 2, 01.02.2018, p. 122-130.

Research output: Contribution to journalArticle

Ben-Salem, S, Robbins, SM, Sobreira, N, Lyon, A, Al-Shamsi, AM, Islam, BK, Akawi, NA, John, A, Thachillath, P, Al Hamed, S, Valle, D, Ali, BR & Al-Gazali, L 2018, 'Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy', Journal of Medical Genetics, vol. 55, no. 2, pp. 122-130. https://doi.org/10.1136/jmedgenet-2017-104827
Ben-Salem, Salma ; Robbins, Sarah M. ; Sobreira, Nara ; Lyon, Angeline ; Al-Shamsi, Aisha M. ; Islam, Barira K. ; Akawi, Nadia A. ; John, Anne ; Thachillath, Pramathan ; Al Hamed, Sania ; Valle, David ; Ali, Bassam R. ; Al-Gazali, Lihadh. / Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy. In: Journal of Medical Genetics. 2018 ; Vol. 55, No. 2. pp. 122-130.
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abstract = "Background Bone dysplasias are a large group of disorders affecting the growth and structure of the skeletal system. Methods In the present study, we report the clinical and molecular delineation of a new form of syndromic autosomal recessive spondylometaphyseal dysplasia (SMD) in two Emirati first cousins. They displayed postnatal growth deficiency causing profound limb shortening with proximal and distal segments involvement, narrow chest, radiological abnormalities involving the spine, pelvis and metaphyses, corneal clouding and intellectual disability. Whole genome homozygosity mapping localised the genetic cause to 11q12.1-q13.1, a region spanning 19.32 Mb with ∼490 genes. Using whole exome sequencing, we identified four novel homozygous variants within the shared block of homozygosity. Pathogenic variants in genes involved in phospholipid metabolism, such as PLCB4 and PCYT1A, are known to cause bone dysplasia with or without eye anomalies, which led us to select PLCB3 as a strong candidate. This gene encodes phospholipase C β 3, an enzyme that converts phosphatidylinositol 4,5 bisphosphate (PIP 2) to inositol 1,4,5 triphosphate (IP 3) and diacylglycerol. Results The identified variant (c.2632G>T) substitutes a serine for a highly conserved alanine within the Ha2' element of the proximal C-terminal domain. This disrupts binding of the Ha2' element to the catalytic core and destabilises PLCB3. Here we show that this hypomorphic variant leads to elevated levels of PIP 2 in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton. Conclusions Our results connect a homozygous loss of function variant in PLCB3 with a new SMD associated with corneal dystrophy and developmental delay (SMDCD).",
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T1 - Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy

AU - Ben-Salem, Salma

AU - Robbins, Sarah M.

AU - Sobreira, Nara

AU - Lyon, Angeline

AU - Al-Shamsi, Aisha M.

AU - Islam, Barira K.

AU - Akawi, Nadia A.

AU - John, Anne

AU - Thachillath, Pramathan

AU - Al Hamed, Sania

AU - Valle, David

AU - Ali, Bassam R.

AU - Al-Gazali, Lihadh

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Background Bone dysplasias are a large group of disorders affecting the growth and structure of the skeletal system. Methods In the present study, we report the clinical and molecular delineation of a new form of syndromic autosomal recessive spondylometaphyseal dysplasia (SMD) in two Emirati first cousins. They displayed postnatal growth deficiency causing profound limb shortening with proximal and distal segments involvement, narrow chest, radiological abnormalities involving the spine, pelvis and metaphyses, corneal clouding and intellectual disability. Whole genome homozygosity mapping localised the genetic cause to 11q12.1-q13.1, a region spanning 19.32 Mb with ∼490 genes. Using whole exome sequencing, we identified four novel homozygous variants within the shared block of homozygosity. Pathogenic variants in genes involved in phospholipid metabolism, such as PLCB4 and PCYT1A, are known to cause bone dysplasia with or without eye anomalies, which led us to select PLCB3 as a strong candidate. This gene encodes phospholipase C β 3, an enzyme that converts phosphatidylinositol 4,5 bisphosphate (PIP 2) to inositol 1,4,5 triphosphate (IP 3) and diacylglycerol. Results The identified variant (c.2632G>T) substitutes a serine for a highly conserved alanine within the Ha2' element of the proximal C-terminal domain. This disrupts binding of the Ha2' element to the catalytic core and destabilises PLCB3. Here we show that this hypomorphic variant leads to elevated levels of PIP 2 in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton. Conclusions Our results connect a homozygous loss of function variant in PLCB3 with a new SMD associated with corneal dystrophy and developmental delay (SMDCD).

AB - Background Bone dysplasias are a large group of disorders affecting the growth and structure of the skeletal system. Methods In the present study, we report the clinical and molecular delineation of a new form of syndromic autosomal recessive spondylometaphyseal dysplasia (SMD) in two Emirati first cousins. They displayed postnatal growth deficiency causing profound limb shortening with proximal and distal segments involvement, narrow chest, radiological abnormalities involving the spine, pelvis and metaphyses, corneal clouding and intellectual disability. Whole genome homozygosity mapping localised the genetic cause to 11q12.1-q13.1, a region spanning 19.32 Mb with ∼490 genes. Using whole exome sequencing, we identified four novel homozygous variants within the shared block of homozygosity. Pathogenic variants in genes involved in phospholipid metabolism, such as PLCB4 and PCYT1A, are known to cause bone dysplasia with or without eye anomalies, which led us to select PLCB3 as a strong candidate. This gene encodes phospholipase C β 3, an enzyme that converts phosphatidylinositol 4,5 bisphosphate (PIP 2) to inositol 1,4,5 triphosphate (IP 3) and diacylglycerol. Results The identified variant (c.2632G>T) substitutes a serine for a highly conserved alanine within the Ha2' element of the proximal C-terminal domain. This disrupts binding of the Ha2' element to the catalytic core and destabilises PLCB3. Here we show that this hypomorphic variant leads to elevated levels of PIP 2 in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton. Conclusions Our results connect a homozygous loss of function variant in PLCB3 with a new SMD associated with corneal dystrophy and developmental delay (SMDCD).

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