Molecular characterization of leukocyte adhesion deficiency-I in Indian patients: Identification of 9 novel mutations

Madkaikar, Manisha; Italia, Khushnooma; Gupta, Maya; Chavan, Sushant; Mishra, Anju; Rao, Madu; Mhatre, Snehal; Desai, Mukesh; Manglani, Mamta; Singh, Surjit; Suri, Deepti; Agrawal, Amita; Ghosh, Kanjaksha

doi:10.1016/j.bcmd.2015.01.012

Cited by 19 publications

(17 citation statements)

References 39 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also, unusual organisms like Proteus sp., Citrobacter sp., Stingomonas paucimobilis, and Acinetobacter baumani were noted in a few patients. Direct Sanger sequencing of the ITGb2 gene revealed 57 disease-causing variants in 105 patients (Table S2), including 30 patients we have previously reported (18). These mutations were clustered mostly in exons 6 (22%) and exon 7 (11%).…”

Section: Clinical and Genetic Characteristics Of Leukocyte Adhesion Dmentioning

confidence: 97%

“…These patients also have severe recurrent bacterial infections, persistent leukocytosis, and delayed umbilical cord fall with a platelet aggregation defect that results in severe bleeding manifestation (17). Though individual case reports and small case series are available from India (18)(19)(20)(21)(22)(23), there is a paucity of data on the clinical, immunological, and molecular spectrum in LAD. In this study, we report a retrospective cohort study of 132 patients LAD patients from 28 different centers of India.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Clinical and Genetic Spectrum of a Large Cohort of Patients With Leukocyte Adhesion Deficiency Type 1 and 3: A Multicentric Study From India

et al. 2020

Self Cite

View full text Add to dashboard Cite

Leukocyte adhesion deficiency (LAD) syndrome is a group of inborn errors of immunity characterized by a defect in the cascade of the activation and adhesion leading to the failure of leukocyte to migrate to the site of tissue injury. Three different types of LAD have been described. The most common subtype is LAD type 1 (LAD1) caused due to defects in the ITGβ2 gene. LAD type 2 (LAD2) is caused by mutations in the SLC35C1 gene leading to a generalized loss of expression of fucosylated glycans on the cell surface and LAD type 3 (LAD3) is caused by mutations in the FERMT3 gene resulting in platelet function defects along with immunodeficiency. There is a paucity of data available from India on LAD syndromes. The present study is a retrospective analysis of patients with LAD collated from 28 different centers across India. For LAD1, the diagnosis was based on clinical features and flow cytometric expression of CD18 on peripheral blood leukocytes and molecular confirmation by Sanger sequencing. For patients with LAD3 diagnosis was largely based on clinical manifestations and identification of the pathogenic mutation in the FERMT3 gene by next-generation Sequencing. Of the total 132 cases diagnosed with LAD, 127 were LAD1 and 5 were LAD3. The majority of our patients (83%) had CD18 expression less than 2% on neutrophils (LAD1°) and presented within the first three months of life with omphalitis, skin and soft tissue infections, delayed umbilical cord detachment, otitis media, and sepsis. The patients with CD18 expression of more than 30% (LAD1+) presented later in life with skin ulcers being the commonest manifestation. Bleeding manifestations were common in patients with LAD3. Persistent neutrophilic leukocytosis was the characteristic finding in all patients. 35 novel mutations were detected in the ITGβ2 gene, and 4 novel mutations were detected in the FERMT3 gene. The study thus presents one of the largest cohorts of patients from India with LAD, focusing on clinical features, immunological characteristics, and molecular spectrum.

show abstract

Section: Clinical and Genetic Characteristics Of Leukocyte Adhesion Dmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Clinical and Genetic Spectrum of a Large Cohort of Patients With Leukocyte Adhesion Deficiency Type 1 and 3: A Multicentric Study From India

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is the von Willebrand Factor type A (VWFA) domain that forms the extracellular domain of CD18 protein and is critical for the structural association of α and β integrin subunits for heterodimer formation on the cell surface and functional activity. It suggests that any significant alterations in the amino acid sequence in this region will have a deleterious effect on the expression and functional activity of CD18 antigen (Madkaikar et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Better understanding the molecular characterization of this disease is necessary to increase awareness and identification of infants with LAD1. Though LAD1 has been studied, so far only 500 cases and 126 mutations in ITGB2 have been reported (Madkaikar et al, 2015). And now, whole exome sequencing (WES) has become a more cost-effective and faster tool for analysis of the disease-causing mutations in many genetic diseases including LAD1.…”

Section: Introductionmentioning

confidence: 99%

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

Liên

Anh

Tung

et al. 2022

Vietnam J. Biotechnol.

View full text Add to dashboard Cite

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.

show abstract

“…However, the produced B cells are functionally defective in X-linked SCID. It accounts for 40-50% of all cases [3]. The defect lies in IL-2 receptor γ-chain mutations which lead to a very low number of T-cells and NK-cells in circulation.…”

Section: T-b+ Scidmentioning

confidence: 99%

Untitled

2018

Natl. j. health sci.

View full text Add to dashboard Cite

Molecular characterization of leukocyte adhesion deficiency-I in Indian patients: Identification of 9 novel mutations

Cited by 19 publications

References 39 publications

Clinical and Genetic Spectrum of a Large Cohort of Patients With Leukocyte Adhesion Deficiency Type 1 and 3: A Multicentric Study From India

Clinical and Genetic Spectrum of a Large Cohort of Patients With Leukocyte Adhesion Deficiency Type 1 and 3: A Multicentric Study From India

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

Untitled

Contact Info

Product

Resources

About