A novel nonsense mutation in ADAMTS17 caused autosomal recessive inheritance Weill–Marchesani syndrome from a Chinese family

Abstract

Weill–Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, eye anomalies, including microspherophakia, ectopia of the lenses, severe myopia, glaucoma and occasionally heart defects. Given these complex clinical manifestations and genetic heterogeneity, WMS patients presented misdiagnosed as high myopia or angle closure glaucoma. Here, we report ADAMTS17 mutations, a member of the extracellular matrix protease family, from a Chinese family. Patients have features that fall within the WMS spectrum. The exome (protein-coding regions of the genome) makes up ~1 % of the genome, it contains about 85% of known disease-related variants. Whole exome sequencing (WES) has been performed to identify the disease-associated genes, including one patient, his healthy sister, and his asymptomatic wife. Genome-wide homozygosity map was used to identify the disease caused locus. SNVs and INDELs were further predicted with MutationTaster, LRT, SIFT and SiPhy and compared to dbSNP150 and 1000 Genomes project. Filtered mutation was confirmed with Sanger sequencing in whole family members. The Genome-wide homozygosity map based on WES identified a total of 20 locus which were possible pathogenic. Further, a novel nonsense mutation c.1051A >T result in p.(lys351Ter) in ADAMTS17 had been identified in a candidate loci. The Sanger sequencing data has verified two consanguineous WMS patients in the family pedigree and revealed autosomal recessive (AR) inheritance pattern. The nonsense mutation in ADAMTS17 was analyzed in silico to explore its effects on protein function. We predicted the mutation produced non-function protein sequence. A novel nonsense mutation c.1051 A > T in ADAMTS17 had been identified caused autosomal recessive WMS in the Chinese family.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Data availability

The datasets collected and/or analyzed during the current study are available from the corresponding author upon reasonable request. Please contact author for data requests.

References

  1. 1.

    Dagoneau N, Benoist-Lasselin C, Huber C, Faivre L, Megarbane A, Alswaid A, et al. ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am J Hum Genet. 2004;75:801–6.

    CAS  Article  Google Scholar 

  2. 2.

    Faivre L, Gorlin RJ, Wirtz MK, Godfrey M, Dagoneau N, Samples JR, et al. In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J Med Genet. 2003;40:34–6.

    CAS  Article  Google Scholar 

  3. 3.

    Wang LW, Kutz WE, Mead TJ, Beene LC, Singh S, Jenkins MW, et al. Adamts10 inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage. Matrix Biol. 2019;77:117–128

    CAS  Article  Google Scholar 

  4. 4.

    Morales J, Al-Sharif L, Khalil DS, Shinwari JM, Bavi P, Al-Mahrouqi RA, et al. Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Am J Hum Genet. 2009;85:558–68.

    CAS  Article  Google Scholar 

  5. 5.

    Haji-Seyed-Javadi R, Jelodari-Mamaghani S, Paylakhi SH, Yazdani S, Nilforushan N, Fan JB, et al. LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. Hum Mutat. 2012;33:1182–7.

    CAS  Article  Google Scholar 

  6. 6.

    Gibson MA, Hatzinikolas G, Davis EC, Baker E, Sutherland GR, Mecham RP. Bovine latent transforming growth factor beta 1-binding protein 2: molecular cloning, identification of tissue isoforms, and immunolocalization to elastin-associated microfibrils. Mol Cell Biol. 1995;15:6932–42.

    CAS  Article  Google Scholar 

  7. 7.

    Hirani R, Hanssen E, Gibson MA. LTBP-2 specifically interacts with the amino-terminal region of fibrillin-1 and competes with LTBP-1 for binding to this microfibrillar protein. Matrix biology: journal of the International Society for. Matrix Biol. 2007;26:213–23.

    CAS  Article  Google Scholar 

  8. 8.

    Le Goff C, Cormier-Daire V. The ADAMTS(L) family and human genetic disorders. Hum Mol Genet. 2011;20:R163–7.

    Article  Google Scholar 

  9. 9.

    Faivre L, Dollfus H, Lyonnet S, Alembik Y, Megarbane A, Samples J, et al. Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome. Am J Med Genet Part A. 2003;123a:204–7.

    Article  Google Scholar 

  10. 10.

    Adams DR, Eng CM. Next-Generation Sequencing to Diagnose Suspected Genetic Disorders. New Engl J Med. 2019;380:201.

    PubMed  Google Scholar 

  11. 11.

    Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic acids Res. 2010;38:e164.

    Article  Google Scholar 

  12. 12.

    Nayak B, Sinha G, Patil B, Khokhar S. Golden ring in the eyes: Weill-Marchesani syndrome. BMJ case reports. 2015;2015.

  13. 13.

    Liu Y, Jing F, Yi W, Mendelson A, Shi P, Walsh R, et al. HO-1(hi) patrolling monocytes protect against vaso-occlusion in sickle cell disease. Blood. 2018;131:1600–10.

    CAS  Article  Google Scholar 

  14. 14.

    Porter S, Clark IM, Kevorkian L, Edwards DR. The ADAMTS metalloproteinases. Biochem J. 2005;386:15–27.

    CAS  Article  Google Scholar 

  15. 15.

    Dubail J, Apte SS. Insights on ADAMTS proteases and ADAMTS-like proteins from mammalian genetics. Matrix biology: journal of the International Society for. Matrix Biol. 2015;44-46:24–37.

    CAS  Article  Google Scholar 

  16. 16.

    Lango Allen H, Estrada K, Lettre G, Berndt SI, Weedon MN, Rivadeneira F, et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature. 2010;467:832–8.

    CAS  Article  Google Scholar 

  17. 17.

    van Duyvenvoorde HA, Lui JC, Kant SG, Oostdijk W, Gijsbers AC, Hoffer MJ, et al. Copy number variants in patients with short stature. Eur J Hum Genet. 2014;22:602–9.

    Article  Google Scholar 

  18. 18.

    Kutz WE, Wang LW, Bader HL, Majors AK, Iwata K, Traboulsi EI, et al. ADAMTS10 protein interacts with fibrillin-1 and promotes its deposition in extracellular matrix of cultured fibroblasts. J Biol Chem. 2011;286:17156–67.

    CAS  Article  Google Scholar 

  19. 19.

    Gould D, Pettitt L, McLaughlin B, Holmes N, Forman O, Thomas A, et al. ADAMTS17 mutation associated with primary lens luxation is widespread among breeds. Vet Ophthalmol. 2011;14:378–84.

    CAS  Article  Google Scholar 

  20. 20.

    Forman OP, Pettitt L, Komaromy AM, Bedford P, Mellersh C. A Novel genome-wide association study approach using genotyping by exome sequencing leads to the identification of a primary open angle glaucoma associated inversion disrupting ADAMTS17. PLoS ONE. 2015;10:e0143546.

    Article  Google Scholar 

  21. 21.

    Oliver JA, Forman OP, Pettitt L, Mellersh CS. Two independent mutations in ADAMTS17 are associated with primary open angle glaucoma in the basset hound and basset fauve de bretagne breeds of dog. PLoS ONE. 2015;10:e0140436.

    Article  Google Scholar 

  22. 22.

    Shah MH, Bhat V, Shetty JS, Kumar A. Whole exome sequencing identifies a novel splice-site mutation in ADAMTS17 in an Indian family with Weill-Marchesani syndrome. Mol vision. 2014;20:790–6.

    Google Scholar 

  23. 23.

    Khan AO, Aldahmesh MA, Al-Ghadeer H, Mohamed JY, Alkuraya FS. Familial spherophakia with short stature caused by a novel homozygous ADAMTS17 mutation. Ophthalmic Genet. 2012;33:235–9.

    CAS  Article  Google Scholar 

  24. 24.

    Radner FP, Marrakchi S, Kirchmeier P, Kim GJ, Ribierre F, Kamoun B, et al. Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. PLoS Genet. 2013;9:e1003536.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We would like to thank all of the study participants for their commitment. This work was supported by National Natural Science Foundation of China (#31760308, #81860173).

Author contributions

YSH and HAY conceived designed, review and editing the study. XZ and YCZ conducted the experiments. HAY, XZ, JL, SZH, YBK, GJW and YLY collected the data, processed data analysis and interpretation of data. HAY wrote the original manuscript. YSH critically revising the article. All authors reviewed and approved the final manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yongshu He.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Editorial policies and ethical consideration

The current study was approved by the Institutional Review Boards of Kunming Medical University. Written informed consent was obtained from all investigated individuals prior to the study. Before enrollment, the patients or their guardians gave informed consent.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yi, H., Zha, X., Zhu, Y. et al. A novel nonsense mutation in ADAMTS17 caused autosomal recessive inheritance Weill–Marchesani syndrome from a Chinese family. J Hum Genet 64, 681–687 (2019). https://doi.org/10.1038/s10038-019-0608-2

Download citation

Further reading