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SCIENCE CHINA Life Sciences, Volume 60 , Issue 1 : 57-65(2017) https://doi.org/10.1007/s11427-016-0333-3

Variants of genes encoding collagens and matrix metalloproteinase system increased the risk of aortic dissection

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  • ReceivedOct 9, 2016
  • AcceptedNov 1, 2016
  • PublishedDec 13, 2016

Abstract

Aortic dissection (AD) is a devastating, heterogeneous condition of aorta. The homeostasis between collagens and matrix metalloproteases (MMPs)/tissue inhibitors of MMPs (TIMPs) system in the extracellular matrix plays an important role for structure and functions of aorta. However, our knowledge on association between variants of genes in this system and pathogenesis of AD is very limited. We analyzed all yet known coding human genes of collagens (45 genes), MMPs/TIMPs (27 genes) in 702 sporadic AD patients and in 163 matched healthy controls, by using massively targeted next-generation and Sanger sequencing. To define the pathogenesis of potential disease-causing candidate genes, we performed transcriptome sequencing and pedigree co-segregation analysis in some genes and generated Col5a2 knockout rats. We identified 257 pathogenic or likely pathogenic variants which involved 88.89% (64/72) genes in collagens-MMPs/TIMPs system and accounted for 31.05% (218/702) sporadic AD patients. In them, 84.86% patients (185/218) carried one variant, 12.84% two variants and 2.30% more than two variants. Importantly, we identified 52 novel probably pathogenic loss-of-function (LOF) variants (20 nonsense, 16 frameshift, 14 splice sites, one stop-loss, one initiation codon) in 11.06% (50/452) AD patients, which were absent in 163 controls (P=2.5×10−5). Transcriptome sequencing revealed that identified variants induced dyshomeostasis in expression of collagens-TIMPs/MMPs systems. The Col5a2−/− rats manifested growth retardation and aortic dysplasia. Our study provides a first comprehensive map of genetic alterations in collagens-MMPs/TIMPs system in sporadic AD patients and suggests that variants of these genes contribute largely to AD pathogenesis.


Funded by

National Natural Science Foundation of China(91439203)

National Key Basic Research Program of China(2012CB518004,2012CB517801)


Acknowledgment

We thank Drs. Mingjia Ma and Zeming Fang for their efforts in recruiting patients for this study. We especially acknowledge all the participants in this study. This work was supported by the National Natural Science Foundation of China (91439203), and National Key Basic Research Program of China (2012CB518004, 2012CB517801).


Interest statement

The author(s) declare that they have no conflict of interest.


Supplement

SUPPORTING INFORMATION

Figure S1 Normalized expression level of top 15 genes.

Figure S2 The mRNA differentially expression level of 12 novel identified LOF or likely pathogenic variants in AD cases.

Table S1 Known pathogenic genes for AD

Table S2 Likely pathogenic variants in collagens and MMPs/TIMPs coding genes for 702 AD patients

Table S3 Collagens and MMPs/TIMPs coding genes

The supporting information is available online at life.scichina.com and www.springerlink.com. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.


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  • Figure 1

    The LOF and likely pathogenic variants identified in 702 AD cases. This panel shows the 54 novel identified LOF and likely pathogenic variants identified in 702 AD patients of collagens and MMPs/TIMPs genes. The LOF variants are shown in black and likely pathogenic variants are shown in red.

  • Figure 2

    Correlations between phenotype and genotype. A, Average onsetage of AD patients carried different number of pathogenic or likely pathogenic variants. The error bars indicate standard error (SE). *, P<0.05. B, Percentage of DeBaKey type 3 AD cases in different number of pathogenic or likely pathogenic variants. C, Average onsetage of AD patients carried pathogenic or likely pathogenic variants in different genes. The error bars indicate standard error (SE). D, Percentage of DeBaKey type 3 AD cases in different genes.

  • Figure 3

    Pedigree co-segregation analysis. A, The pedigree co-segregation analysis of a COL14A1 nonsense variant carried AD patient (AD337). B, The pedigree co-segregation analysis of a COL6A5 frameshift deletion variant carried AD patient (AD606).

  • Figure 4

    The histological staining of a thoracic aortic lesion region of Col5a2/ rat and control at nine weeks. A, Sirius red staining of the thoracic aortic lesion region of Col5a2/ rat. Bar=200 µm. B, Sirius red staining of the thoracic aortic of a wild type rat. Bar=200 µm. C, Higher magnification of the lesion region of the arterial wall of a Col5a2/ rat showing less elastin fibers in the loose hyperplasia media. Bar=50 µm. D, Higher magnification of the control artery. Bar=50 µm. E, The thoracic aortic lesion region of a Col5a2/ rat was stained with mouse anti-α-smooth muscle actin. Arrow indicates loss of smooth muscle cells in the lesion region of the media. Bar=50 µm. F, Van Gieson staining of the thoracic aortic lesion region of a Col5a2/ rat. Arrow indicates loss, disarray and fragmentation of the elastin fibers in the lesion region of the media. Bar=50 µm.

  • Table 1   LOF and pathogenic variants in collagens and MMPs/TIMPs coding genes for 702 AD patients

    Count*

    Gene name

    Variant function

    Protein change

    Coding change

    Novelty

    1

    COL10A1

    Initiation codon

    p.Met1Thr

    c.2T>C

    Novel

    1

    COL12A1

    Nonsense

    p.Arg3035Ter

    c.9103C>T

    Novel

    1

    COL14A1

    Nonsense

    p.Arg1473Ter

    c.4417C>T

    Novel

    1

    COL16A1

    Frameshift deletion

    p.Gln992fs

    c.2974_2974delC

    Novel

    1

    COL16A1

    Splicesite_5

    chr1:32155995_32155996delCT

    Novel

    1

    COL18A1

    Frameshift insertion

    p.Pro1286fs

    c.3852_3853insCA

    Novel

    1

    COL18A1

    Frameshift insertion

    p.Asp1296fs

    c.3885_3886insC

    Novel

    1

    COL18A1

    Nonsense

    p.Glu378Ter

    c.1132G>T

    Novel

    1

    COL18A1

    Splicesite_5

    chr21:46912599A>G

    Novel

    2

    COL20A1

    Frameshift insertion

    p.Leu613fs

    c.1835_1836insCGG

    Novel

    1

    COL21A1

    Frameshift insertion

    p.Tyr392fs

    c.1173_1174insA

    Novel

    1

    COL21A1

    Splicesite_3

    chr6:55929375C>T

    Novel

    1

    COL24A1

    Frameshift deletion

    p.Glu450fs

    c.1347_1347delA

    Novel

    1

    COL24A1

    Nonsense

    p.Arg1206Ter

    c.3616C>T

    rs187705574

    1

    COL28A1

    Frameshift deletion

    p.Ser1020fs

    c.3059_3059delC

    Novel

    1

    COL2A1

    Splicesite_5

    chr12:48373349_48373350delTG

    Novel

    2

    COL3A1

    Missense

    p.Ala1259Val

    c.3776C>T

    CM122891**

    1

    COL3A1

    Splicesite_3

    chr2:189868871T>A

    Novel

    1

    COL4A3

    Frameshift Block substitution

    p.Pro553fs

    c.1657_1664delCCAGGTGAinsT

    Novel

    1

    COL4A4

    Stoploss

    p.Ter1691Tyr

    c.5073G>C

    Novel

    1

    COL5A2

    Splicesite_3

    chr2:189922044A>T

    Novel

    1

    COL5A3

    Splicesite_5

    chr19:10099854C>G

    Novel

    1

    COL6A3

    Nonsense

    p.Gln1760Ter

    c.5278C>T

    Novel

    1

    COL6A5

    Frameshift deletion

    p.Arg1384fs

    c.4146_4147delAG

    Novel

    1

    COL6A5

    Frameshift insertion

    p.Ala568fs

    c.1699_1700insG

    Novel

    1

    COL6A5

    Splicesite_3

    chr3:130188326G>T

    Novel

    1

    COL6A5

    Splicesite_5

    chr3:130098259A>G

    Novel

    4

    COL6A6

    Nonsense

    p.Arg1480Ter

    c.4438A>T

    rs140413590

    2

    COL6A6

    Splicesite_3

    chr3:130318654_130318657delAGTA

    Novel

    1

    COL7A1

    Frameshift insertion

    p.Gly2233fs

    c.6696_6697insC

    Novel

    1

    COL7A1

    Nonsense

    p.Arg1343Ter

    c.4027C>T

    Novel

    1

    COL8A1

    Nonsense

    |p.Arg225Ter

    c.673C>T

    Novel

    1

    MMP1

    Frameshift deletion

    p.Asp408fs

    c.1222_1222delG

    Novel

    1

    MMP1

    Splicesite_3

    chr11:102663334A>T

    Novel

    1

    MMP1

    Splicesite_5

    chr11:102661539T>C

    Novel

    1

    MMP10

    Frameshift deletion

    p.Asp193fs

    c.576_580delAGATA

    Novel

    1

    MMP17

    Frameshift deletion

    p.Tyr512fs

    c.1534_1534delT

    Novel

    2

    MMP19

    Nonsense

    p.Arg408Ter

    c.1222C>T

    Novel

    4

    MMP19

    Nonsense

    p.Gln5Ter

    c.13C>T

    rs17844787

    1

    MMP27

    Nonsense

    p.Gln330Ter

    c.988C>T

    Novel

    1

    MMP28

    Nonsense

    p.Arg391Ter

    c.1173C>T

    Novel

    1

    MMP28

    Nonsense

    p.Gln49Ter

    c.145C>T

    Novel

    1

    MMP8

    Frameshift deletion

    p.Lys39fs

    c.117_117delG

    Novel

    1

    MMP8

    Splicesite_5

    chr11:102584189C>T

    Novel

    *, indicates count of the variants in AD patients; **, CM122891 is the pathogenic number in HGMD database.

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