Genotype-Phenotype Correlation of 2q37 Deletions Including NPPC Gene Associated with Skeletal Malformations

Tassano, Elisa; Buttgereit, Jens; Bäder, Michael; Lerone, Margherita; Divizia, Maria Teresa; Bocciardi, Renata; Napoli, Flavia; Pala, Giovanna; Sloan‐Béna, Frédérique; Gimelli, Stefania; Gimelli, Giorgio

doi:10.1371/journal.pone.0066048

Cited by 35 publications

(33 citation statements)

References 18 publications

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“…Germline mutations in these children are consistent with a loss of function of Dis3L2 12 . In addition, a truncation of the DIS3L2 locus has been associated with a Marfan-like syndrome with skeletal overgrowth 15 . Dis3L2 is also likely to be important in sporadic Wilms' tumor as 30% of these tumors (6/20) show partial or complete DIS3L2 deletion 12 .…”

Section: Introductionmentioning

confidence: 75%

A novel role for the 3′-5′ exoribonuclease Dis3L2 in controlling cell proliferation and tissue growth

et al. 2016

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In a complex organism, cell proliferation and apoptosis need to be precisely controlled in order for tissues to develop correctly. Excessive cell proliferation can lead to diseases such as cancer. We have shown that the exoribonuclease Dis3L2 is required for the correct regulation of proliferation in a natural tissue within the model organism Drosophila melanogaster. Dis3L2 is a member of a highly conserved family of exoribonucleases that degrade RNA in a 3′-5′ direction. We show that knockdown of dis3L2 in the Drosophila wing imaginal discs results in substantial wing overgrowth due to increased cellular proliferation rather than an increase in cell size. Imaginal discs are specified in the embryo before proliferating and differentiating to form the adult structures of the fly. Using RNA-seq we identified a small set of mRNAs that are sensitive to Dis3L2 activity. Of the mRNAs which increase in levels and are therefore potential targets of Dis3L2, we identified 2 that change at the post-transcriptional level but not at the transcriptional level, namely CG2678 (a transcription factor) and pyrexia (a TRP cation channel). We also demonstrate a compensatory effect between Dis3L2 and the 5′-3′ exoribonuclease Pacman demonstrating that these 2 exoribonucleases function to regulate opposing pathways within the developing tissue. This work provides the first description of the molecular and developmental consequences of Dis3L2 inactivation in a non-human animal model. The work is directly relevant to the understanding of human overgrowth syndromes such as Perlman syndrome.

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Section: Introductionmentioning

confidence: 75%

A novel role for the 3′-5′ exoribonuclease Dis3L2 in controlling cell proliferation and tissue growth

et al. 2016

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“…Large mutations with breakpoints within Dis3l2 have been found in humans with extreme skeletal phenotypes (Tassano et al. ), moreover an SNP (rs3103296) found within the gene was associated with human height (Lanktree et al. ).…”

Section: Discussionmentioning

confidence: 99%

“…The LG/J and SM/J strains were independently derived by selection for large (Goodale ; Tassano et al. ) and small body size (MacArthur ; Chai ), respectively, and offer a particularly useful model. Specifically, these strains differ in long‐bone length, biomechanical and structural proprieties of the bones (Reich et al.…”

Section: Introductionmentioning

confidence: 99%

“…The genetics underlying variation in health-related musculoskeletal phenotypes can be investigated in mouse models (Lionikas et al 2010;Carbonetto et al 2014;Parker et al 2016). The LG/J and SM/J strains were independently derived by selection for large (Goodale 1938;Tassano et al 2013) and small body size (MacArthur 1944;Chai 1956), respectively, and offer a particularly useful model. Specifically, these strains differ in long-bone length, biomechanical and structural proprieties of the bones (Reich et al 2008;Norgard et al 2011), metabolic traits (Nikolskiy et al 2015), muscle mass (Lionikas et al 2010, and characteristics of muscle fibers (Carroll et al , 2017.…”

Section: Introductionmentioning

confidence: 99%

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Replication and discovery of musculoskeletal QTLs in LG/J and SM/J advanced intercross lines

et al. 2018

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The genetics underlying variation in health-related musculoskeletal phenotypes can be investigated in a mouse model. Quantitative trait loci (QTLs) affecting musculoskeletal traits in the LG/J and SM/J strain lineage remain to be refined and corroborated. The aim of this study was to map muscle and bone traits in males (n = 506) of the 50th filial generation of advanced intercross lines (LG/SM AIL) derived from the two strains. Genetic contribution to variation in all musculoskeletal traits was confirmed; the SNP heritability of muscle mass ranged between 0.46 and 0.56; and the SNP heritability of tibia length was 0.40. We used two analytical software, GEMMA and QTLRel, to map the underlying QTLs. GEMMA required substantially less computation and recovered all the QTLs identified by QTLRel. Seven significant QTLs were identified for muscle weight (Chr 1, 7, 11, 12, 13, 15, and 16), and two for tibia length, (Chr 1 and 13). Each QTL explained 4-5% of phenotypic variation. One muscle and both bone loci replicated previous findings; the remaining six were novel. Positional candidates for the replicated QTLs were prioritized based on in silico analyses and gene expression in muscle tissue. In summary, we replicated existing QTLs and identified novel QTLs affecting muscle weight, and replicated bone length QTLs in LG/SM AIL males. Heritability estimates substantially exceed the cumulative effect of the QTLs, hence a richer genetic architecture contributing to muscle and bone variability could be uncovered with a larger sample size.

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“…In humans, overexpression of CNP results in overgrowth [42, 43]. Conversely, homozygous inactivating mutations in natriuretic peptide receptor 2 ( NPR2 ), the primary receptor for CNP, cause acromesomelic dysplasia, Maroteaux type [44], whereas heterozygous mutations can present as idiopathic short stature with no or only subtle signs of a skeletal dysplasia [45, 46].…”

Section: Molecular Mechanism Involved In Longitudinal Growthmentioning

confidence: 99%

New Genetic Diagnoses of Short Stature Provide Insights into Local Regulation of Childhood Growth

2017

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Idiopathic short stature is a common condition with a heterogeneous etiology. Advances in genetic methods, including genome sequencing techniques and bioinformatics approaches, have emerged as important tools to identify the genetic defects in families with monogenic short stature. These findings have contributed to the understanding of growth regulation and indicate that growth plate chondrogenesis, and therefore linear growth, is governed by a large number of genes important for different signaling pathways and cellular functions, including genetic defects in hormonal regulation, paracrine signaling, cartilage matrix, and fundamental cellular processes. In addition, mutations in the same gene can cause a wide phenotypic spectrum depending on the severity and mode of inheritance of the mutation.

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Genotype-Phenotype Correlation of 2q37 Deletions Including NPPC Gene Associated with Skeletal Malformations

Cited by 35 publications

References 18 publications

A novel role for the 3′-5′ exoribonuclease Dis3L2 in controlling cell proliferation and tissue growth

A novel role for the 3′-5′ exoribonuclease Dis3L2 in controlling cell proliferation and tissue growth

Replication and discovery of musculoskeletal QTLs in LG/J and SM/J advanced intercross lines

New Genetic Diagnoses of Short Stature Provide Insights into Local Regulation of Childhood Growth

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