Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.10.2 (
focal adhesion kinase
)
44,029
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The precise diagnosis of an immunodeficiency is sometimes difficult to assess, especially due to the large spectrum of phenotypic variation reported among patients. Common variable immunodeficiency disorders (CVID) do not have, for a large part, an identified genetic cause. The identification of a causal genetic mutation is important to confirm, or in some cases correct, the diagnosis. We screened >150 male patients with hypogammaglobulinemia for mutations in three genes involved in pediatric X-linked primary immunoglobulin deficiency: CD40LG, SH2D1A and
BTK
. The SH2D1A screening allowed to reclassify two individuals with an initial CVID presentation as XLP after mutations identification. All these mutations were associated with a lack of protein expression. In addition, 4 patients with a primary diagnosis of CVID and one with a primary
IgG subclass deficiency
were requalified as XLA after identifying
BTK
mutations. Interestingly, two out of these 5 patients carried a damaging coding
BTK
mutation associated with a lower, but detectable,
BTK
expression in monocytes, suggesting that a dysfunctional protein explains the disease phenotype in these patients. In conclusion, our results advocate to include SH2D1A and
BTK
in newly developed targeted NGS genetic testing, to contribute to providing the most appropriate medical treatment and genetic counselling.
...
PMID:Genetic screening of male patients with primary hypogammaglobulinemia can guide diagnosis and clinical management. 2970 55
Background:
Patients with predominantly antibody deficiency (PAD) suffer from severe and recurrent infections that require lifelong immunoglobulin replacement and prophylactic antibiotic treatment. Disease incidence is estimated to be 1:25,000 worldwide, and up to 68% of patients develop non-infectious complications (NIC) including autoimmunity, which are difficult to treat, causing high morbidity, and early mortality. Currently, the etiology of NIC is unknown, and there are no diagnostic and prognostic markers to identify patients at risk.
Objectives:
To identify immune cell markers that associate with NIC in PAD patients.
Methods:
We developed a standardized 11-color flow cytometry panel that was utilized for in-depth analysis of B and T cells in 62 adult PAD patients and 59 age-matched controls.
Results:
Nine males had mutations in
Bruton's tyrosine kinase
(
BTK
) and were defined as having X-linked agammaglobulinemia. The remaining 53 patients were not genetically defined and were clinically diagnosed with agammaglobulinemia (
n
= 1), common variable immunodeficiency (CVID) (
n
= 32), hypogammaglobulinemia (
n
= 13),
IgG subclass deficiency
(
n
= 1), and specific polysaccharide antibody deficiency (
n
= 6). Of the 53, 30 (57%) had one or more NICs, 24 patients had reduced B-cell numbers, and 17 had reduced T-cell numbers. Both PAD-NIC and PAD+NIC groups had significantly reduced Ig class-switched memory B cells and naive CD4 and CD8 T-cell numbers. Naive and IgM memory B cells, Treg, Th17, and Tfh17 cells were specifically reduced in the PAD+NIC group. CD21
lo
B cells and Tfh cells were increased in frequencies, but not in absolute numbers in PAD+NIC.
Conclusion:
The previously reported increased frequencies of CD21
lo
B cells and Tfh cells are the indirect result of reduced naive B-cell and T-cell numbers. Hence, correct interpretation of immunophenotyping of immunodeficiencies is critically dependent on absolute cell counts. Finally, the defects in naive B- and T-cell numbers suggest a mild combined immunodeficiency in PAD patients with NIC. Together with the reductions in Th17, Treg, and Tfh17 numbers, these key differences could be utilized as biomarkers to support definitive diagnosis and to predict for disease progression.
...
PMID:Predominantly Antibody-Deficient Patients With Non-infectious Complications Have Reduced Naive B, Treg, Th17, and Tfh17 Cells. 3180 77
