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 Lm 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

1 Citation (Scopus)

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 (PIP2) to inositol 1,4,5 triphosphate (IP3) 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 PIP2 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).

LanguageEnglish
Pages122-130
Number of pages9
JournalJournal of Medical Genetics
Volume55
Issue number2
Early online date9 Nov 2017
DOIs
Publication statusPublished - 1 Feb 2018
Externally publishedYes

Fingerprint

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

Cite this

Ben-Salem, Salma ; Robbins, Sarah M ; Lm 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 (PIP2) to inositol 1,4,5 triphosphate (IP3) 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 PIP2 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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author = "Salma Ben-Salem and Robbins, {Sarah M} and {Lm Sobreira}, Nara and Angeline Lyon and Al-Shamsi, {Aisha M} and Islam, {Barira K} and Akawi, {Nadia A} and Anne John and Pramathan Thachillath and {Al Hamed}, Sania and David Valle and Ali, {Bassam R} and Lihadh Al-Gazali",
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Ben-Salem, S, Robbins, SM, Lm 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

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; Lm 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

TY - JOUR

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 - Lm 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

N1 - © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

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 (PIP2) to inositol 1,4,5 triphosphate (IP3) 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 PIP2 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 (PIP2) to inositol 1,4,5 triphosphate (IP3) 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 PIP2 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).

KW - disorganization of actin cytoskeletal network

KW - hypomorphic variant

KW - pip2 accumulation

KW - plcb3

KW - spondylometaphyseal dysplasia with corneal dystrophy (smdcd)

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