Differential intolerance to loss of function and missense mutations in genes that encode human matricellular proteins

Kaur, Sukhbir; Roberts, D. A.

doi:10.1007/s12079-020-00598-9

Cited by 3 publications

(8 citation statements)

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“…In contrast to the Thbs1 −/− mouse data, significant deficits in the rates of missense and predicted LoF nonsense mutations in THBS1 were found in the human gnomAD dataset (v2.1.1). Compared to the 56 expected LoF mutants, only 7 were observed, and the pLI for THBS1 was 1.00, indicating this gene to be highly loss‐intolerant (Kaur and Roberts 2021). In addition, none of the 7 individuals with THBS1 LoF mutant alleles were homozygotes.…”

Section: Thbs1 a Nonessential Gene In Mice That Is Intolerant To Lof ...mentioning

confidence: 99%

“…Based on the length of the CCN1 open reading frame, 17.2 LoF mutants were expected among the 141,456 individuals in gnomAD, but only 3 LoF mutants were observed. Therefore, CCN1 had a significantly elevated probability of LoF intolerance (pLI = 0.71) (Kaur and Roberts 2021 ). This is consistent with the essential function of Ccn1 in mouse prenatal development (Mo et al 2002 ; Mo and Lau 2006 ) and establishes that mutation frequency data can be informative for evaluating loss-intolerance for matricellular protein genes in a human population.…”

Section: Are Essential Matricellular Genes In Mice Also Essential In ...mentioning

confidence: 99%

“…Because the relatively short coding sequences of CCN genes limits interpretation of LoF mutants, exome data from a larger population will be needed confirm or exclude intolerance to LoF for CCN members other than CCN1 . We also examined the frequency of missense mutations in the CCN family and found the largest deficits in CCN1 and CCN2 (Kaur and Roberts 2021 ), but again data from additional individuals would be required to confirm significance.…”

Section: Are Essential Matricellular Genes In Mice Also Essential In ...mentioning

confidence: 99%

“…Several matricellular genes that are not essential for viability in mice had significant pLI values in the gnomAD data, including THBS1 , THBS2 , SPARC , SPOCK1 , and TNR (Kaur and Roberts 2021 ). Thbs1 −/− mice are viable, fertile, and appeared healthy except for lung inflammation (Lawler et al 1998 ).…”

Section: Thbs1 a Nonessential Gene In Mice That Is Intolera...mentioning

confidence: 99%

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Why do humans need thrombospondin-1?

Kaur

Roberts

2023

J. Cell Commun. Signal.

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Matricellular proteins comprise several families of secreted proteins that function in higher animals at the interface between cells and their surrounding extracellular matrix. Targeted gene disruptions that result in loss of viability in mice have revealed critical roles for several matricellular proteins in murine embryonic development, including two members of the cellular communication network (CCN) gene family. In contrast, mice lacking single or multiple members of the thrombospondin (THBS) gene family remain viable and fertile. The frequency of loss of function mutants, identified using human deep exome sequencing data, provided evidence that some of the essential genes in mice, including Ccn1, are also essential genes in humans. However, a deficit in loss of function mutants in humans indicated that THBS1 is also highly loss-intolerant. In addition to roles in embryonic development or adult reproduction, genes may be loss-intolerant in humans because their function is needed to survive environmental stresses that are encountered between birth and reproduction. Laboratory mice live in a protected environment that lacks the exposures to pathogens and injury that humans routinely face. However, subjecting Thbs1−/− mice to defined stresses has provided valuable insights into functions of thrombospondin-1 that could account for the loss-intolerance of THBS1 in humans. Graphical Abstract

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Section: Thbs1 a Nonessential Gene In Mice That Is Intolerant To Lof ...mentioning

confidence: 99%

Section: Are Essential Matricellular Genes In Mice Also Essential In ...mentioning

confidence: 99%

Section: Are Essential Matricellular Genes In Mice Also Essential In ...mentioning

confidence: 99%

Section: Thbs1 a Nonessential Gene In Mice That Is Intolera...mentioning

confidence: 99%

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Why do humans need thrombospondin-1?

Kaur

Roberts

2023

J. Cell Commun. Signal.

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“…The Von Willebrand factor type C (VWC) domain is also found in every CCN family member, and the VWC domain most commonly binds to bone morphogenic proteins (BMPs) (Canalis, 2007), TGF-β (Inkson et al, 2008), and diverse integrins (i.e., αMβ2, α2β1, αvβ5, α5β1, α6β1) (Kaur and Roberts, 2021). In CCN2, its interaction with TGF-β enhances TGF-β signaling, such that CCN2 might function as a chaperone for TGF-β, and less TGF-β is required to stimulate downstream signaling (Abreu et al, 2002).…”

Section: Vwc Domain In Ccn Proteinsmentioning

confidence: 99%

CCN Family Proteins in Cancer: Insight Into Their Structures and Coordination Role in Tumor Microenvironment

Jia

Zhang

et al. 2021

Front. Genet.

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The crosstalk between tumor cells and the tumor microenvironment (TME), triggers a variety of critical signaling pathways and promotes the malignant progression of cancer. The success rate of cancer therapy through targeting single molecule of this crosstalk may be extremely low, whereas co-targeting multiple components could be complicated design and likely to have more side effects. The six members of cellular communication network (CCN) family proteins are scaffolding proteins that may govern the TME, and several studies have shown targeted therapy of CCN family proteins may be effective for the treatment of cancer. CCN protein family shares similar structures, and they mutually reinforce and neutralize each other to serve various roles that are tightly regulated in a spatiotemporal manner by the TME. Here, we review the current knowledge on the structures and roles of CCN proteins in different types of cancer. We also analyze CCN mRNA expression, and reasons for its diverse relationship to prognosis in different cancers. In this review, we conclude that the discrepant functions of CCN proteins in different types of cancer are attributed to diverse TME and CCN truncated isoforms, and speculate that targeting CCN proteins to rebalance the TME could be a potent anti-cancer strategy.

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THBS1 is a new autosomal recessive non-syndromic hearing impairment gene

Bharadwaj,

Acharya,

Khan

et al. 2024

BMC Med Genomics

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Background Prelingual hearing impairment (HI) is genetically highly heterogenous. Early diagnosis and intervention are essential for psychosocial development. In this study we investigated a consanguineous family from Pakistan with autosomal recessive (AR) non-syndromic sensorineural HI (NSHI). Methods A DNA sample from an HI member of a consanguineous Pakistani family segregating ARNSHL underwent exome sequencing. Using Sanger sequencing select variants were validated and tested for segregation using DNA samples from additional family members. We further investigated RNA expression data for the candidate gene in mouse and human inner ear and human inner ear organoids using data obtained from the gene Expression Analysis Resource. Results We identified thrombospondin 1 ( THBS1) as a new NSHI gene. A homozygous frameshift variant [c.1470del: p.(Ile491Serfs*45)] was observed in the three hearing-impaired and in the heterozygous state in three unaffected family members. Unlike for most ARNSHI, hearing-impaired individuals had audiograms with a sloping pattern, showing more pronounced HI in the mid and high frequencies (ranging from moderate to profound) compared to the low frequencies. RNA expression data indicates THBS1 is expressed during human inner ear development. Additionally, THBS1 is expressed in the cochlear epithelium and supporting cells of the mouse inner ear during embryonic and postnatal stages. Previously, THBS1 was demonstrated to affect hearing in knockout mice by influencing the formation and function of afferent synapses in the inner ear. Conclusions Our findings highlight THBS1 as a potential novel candidate gene for human HI characterized by a sloping high-frequency audio profile. This discovery enhances our understanding of the genetic etiology of HI and will aid in advancing molecular diagnosis. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-024-02060-w.

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Differential intolerance to loss of function and missense mutations in genes that encode human matricellular proteins

Cited by 3 publications

References 115 publications

Why do humans need thrombospondin-1?

Why do humans need thrombospondin-1?

CCN Family Proteins in Cancer: Insight Into Their Structures and Coordination Role in Tumor Microenvironment

THBS1 is a new autosomal recessive non-syndromic hearing impairment gene

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