Identification of the causative mutation in the ITGB2 gene in a LAD1 patient by whole exome sequencing

Authors

  • Nguyen Thi Kim Lien Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay District, Hanoi, Vietnam
  • Nguyen Thi Van Anh Allergy, Immunology and Rheumatology Department, Vietnam National Hospital of Pediatrics, 18/879 La Thanh, Dong Da District, Hanoi, Vietnam
  • Nguyen Van Tung Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay District, Hanoi, Vietnam
  • Duong Anh Linh Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay District, Hanoi, Vietnam
  • Nguyen Thi Phuong Mai Human Genetics Department, Vietnam National Hospital of Pediatrics, 18/879 La Thanh, Dong Da District, Hanoi, Hanoi, Vietnam
  • Nguyen Huy Hoang Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay District, Hanoi, Vietnam

DOI:

https://doi.org/10.15625/1811-4989/15886

Keywords:

LAD1 patient, mutation, the ITGB2 gene, immunodeficiency, infant, WES

Abstract

Leukocyte adhesion deficiency type 1 (LAD1) is a rare congenital immunodeficiency disease. The cause of disease is determined to be the mutations in the ITGB2 gene that codes for CD18, the beta chain of beta-2 integrins, leads to decreased expression or functioning of CD18. This deficiency leads to severe impairment of leukocyte adhesion to the vascular wall and leukocyte migration to sites of infection and inflammation. LAD1 has also been associated with inhibition of interleukin-23 and interleukin-17 resulting in a hyperinflammatory and chronic inflammation. Patients with LAD1 typically present in early infancy with recurrent, life threatening infections that are frequently fatal before 2 years of age  without hematopoietic stem cell transplant (HSCT). However, LAD1 is difficult to diagnose and many LAD1 patients die at a young age despite intensive antibiotic therapy. Accurate diagnosis requires detailed clinical information (delayed umbilical cord loss, severe periodontitis, delayed wound healing and sores, skin abscesses, and recurrent infection), and confirmation the absence of integrins by flow cytometric analysis. A better understanding of the molecular characteristics of this disease is needed to raise awareness and definitive diagnosis infants with LAD1. To definitive diagnosis, whole exome sequencing and Sanger sequencing were performed in an eighteen-month-old boy with severe leukocytosis, recurrent infections, delayed wound healing, and hepatosplenomegaly associated with an acquired cytomegalovirus infection. Two variants: One previously reported mutation (c.533C>T, p.Pro178Leu) and one novel variant (c.59-1G>A), in the ITGB2 gene were detected. These results can be used for definitive genetic diagnosis, genetic counseling, as well as a prenatal diagnosis in LAD1 patients.

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Author Biography

Nguyen Thi Kim Lien, Institute of Genome Research, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Cau Giay District, Hanoi, Vietnam

Functional Genomics Laboratory

References

Al-Herz W, Bousfiha A, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C, Etzioni A, Fischer A, Franco JL, Geha RS, Hammarstrom L, Nonoyama S, Notarangelo LD, Ochs HD, Puck JM, Roifman CM, Seger R, Tang MLK (2011) Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies expert committee for primary immunodeficiency. Front Immunol 2: 1–26.

Anderson DC, Schmalsteig FC, Finegold MJ, Hughes BJ, Rothlein R, Miller LJ, Kohl S, Tosi MF, Jacobs RL, Waldrop TC, Goldman AS, Shearer WT, Springer TA (1985) The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency: their quantitative definition and relation to leukocyte dysfunction and clinical features. J Infect Dis 152: 668–689.

Etzioni A (2009) Leukocyte adhesion deficiency syndromes. Encyclopedia of Molecucular Mechenisms of Disease: Springer., pp: 1159–1160.

Hanna S, Etzioni A (2012) Leukocyte adhesion deficiencies. Ann NY Acad Sci 1250: 50–55.

Kuijpers TW, Van Lier R, Hamann D, de Boer M, Thung LY, Weening RS, Verhoeven AJ, Roos D (1997) Leukocyte adhesion deficiency type 1 (LAD-1)/variant. A novel immunodeficiency syndrome characterized by dysfunctional beta2 intergrins. J Clin Invest 100: 1725–1733.

Madkaikar M, Italia K, Gupta M, Chavan S, Mishra A, Rao M, Mhatre S, Desai M, Manglani M, Singh S, Suri D, Agrawal A, Ghosh K (2015) Molecular characterization of leukocyte adhesion deficiency-1 in Indian patients: Identification of 9 novel mutations. Blood Cells Mol Dis 54: 217–223.

Mortezaee FT, Esmaeli B, Badalzadeh M, Ghadami M, Fazlollahi MR, Alizade Z, Hamidieh AA, Chavoshzadeh Z, Movahedi M, Heydarzadeh M, Shabestari MS, Tavassoli M, Nabavi M, Kalmarzi RN, Pourpak Z (2015) Investigation of ITGB2 gene in 12 new cases of leukocyte adhesion deficiency-type I revealed four novel mutations from Iran. Arch Iran Med 18(11): 760–764.

Moutsopoulos NM, Konkel J, Sarmadi M, Eskan MA, Wild T, Dutzan N, Abusleme L, Zenobia C, Hosur KB, Abe T, Uzel G, Chen W, Chavakis T, Holland SM, Hajishengallis G (2014) Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss. Sci Transl Med 6(229): 229–240.

Schmidt S, Moser M, Sperandio M (2013) The molecular basis of leukocyte recruitment and its deficiencies. Mol Immunol 55: 49–58.

Schwarz JM, R¨odelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7(8): 575–576.

Shaw JM, Al-Shamkhani A, Boxer LA, Buckley CD, Dodds AW, Klein N, Nolan SM, Roberts I, Roos D, Scarth SI, Simmons DL, Tan SM, Law SKA (2001) Characterization of four CD18 mutants in leukocyte adhesion deficient (LAD) patients with differential capacities to support expression and function of the CD11/CD18 integrins LFA-1, Mac-1 and p150,95. Clin Exp Immunol 126: 311–318.

Springer TA, Thompson WS, Miller LJ, Schmalsteig FC, Anderson DC (1984) Inherited deficiency of the Mac-1, LFA-1, p150,95 glycoprotein family and its molecular basis. J Exp Med 160: 1901–1918.

Thakur H, Sodani R, Chandra J, Singh V (2013) Leukocyte adhesion defect type 1 presenting with recurrent pyoderma gangrenosum. Indian J Dermatol 58: 158.

Tipu HN, Tahir A, Ahmed TA, Hazir T, Waqar MA (2008) Leukocyte adhesion defect. J Pak Med Assoc 58: 643–645.

van de Vijver E, Maddalena A, Sanal O, Holland SM, Uzel G, Madkaikar M, de Boer M, van Leeuwen K, Koker MY, Parvaneh N, Fischer A, Law SKA, Klein N, Tezcan FI, Unal E, Patiroglu T, Belohradsky BH, Schwartz K, Somech R, Kuijpers TW, Roos D (2012) Hematologically important mutations: Leukocyte adhesion deficiency (first update). Blood Cells Mol Dis 48(1): 53–61.

Yashoda-Devi BK, Rakesh N, Devaraju D, Santana N (2011) Leukocyte adhesion deficiency type 1-a focus on oral disease in a young child. Med Oral Patol Oral Cir Bucal 16: 153–157.

Yeo G, Burge CB (2004) Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11(2-3): 377–394.

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Published

2022-06-30

How to Cite

Kim Lien, N. T., Van Anh, N. T., Van Tung, N., Anh Linh, D., Phuong Mai, N. T., & Huy Hoang, N. (2022). Identification of the causative mutation in the ITGB2 gene in a LAD1 patient by whole exome sequencing. Vietnam Journal of Biotechnology, 20(2), 213–218. https://doi.org/10.15625/1811-4989/15886

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