Identification of a compound heterozygous missense mutation in LAMA2 gene from a patient with merosin-deficient congenital muscular dystrophy type 1A.

BACKGROUND: Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is occurred by mutations in LAMA2 gene that encodes the laminin α2 chain (merosin). MDC1A is a predominant subtype of congenital muscular dystrophy. Herein, we identified two missense mutations in LAMA2 gene in compound heterozygous status in an Iranian patient with MDC1A using whole-exome sequencing (WES). METHODS: In the present study, we evaluated genetic alterations in an Iranian 35-month-old boy with MDC1A and his healthy family using WES method. The identified mutations further confirmed by Sanger sequencing method. Finally, in silico analysis was conducted to further evaluation of molecular function of the identified genetic variants. RESULTS: We identified two potentially pathogenic missense mutations in compound heterozygous state (c.7681G>A p.Gly2561Ser and c.4840A>G p.Asn1614Asp) in LAMA2 gene as contributing to the MDC1A phenotype. The healthy parents of our proband are single heterozygous for identified mutations. These variants were found to be pathogenic by in silico analysis. CONCLUSIONS: In general, we successfully identified LAMA2 gene mutations in an Iranian patient with MDC1A using WES. The identified mutations in LAMA2 gene can be useful in genetic counseling, prenatal diagnosis, and predicting prognosis of MDC1A.

Resistance mechanisms to immune checkpoints blockade by monoclonal antibody drugs in cancer immunotherapy: Focus on myeloma.

Multiple myeloma (MM) is a clonal B-cell malignancy characterized by the accumulation of neoplastic proliferation of a plasma cell in the bone marrow that produces a monoclonal immunoglobulin. The immune checkpoint inhibitors against programmed death-1/programmed death-1 ligand and cytotoxic T-lymphocyte antigen 4 axis have demonstrated appropriate anticancer activity in several solid tumors and liquid cancers, and are rapidly transforming the practice of medical oncology. However, in a high percentage of patients, the efficacy of immune checkpoints blockade remains limited due to innate or primary resistance. Moreover, the malignancies progress in many patients due to acquired or secondary resistance, even after the clinical response to immune checkpoints' blockade. The evidence shows that multiple tumor-intrinsic and tumor-extrinsic factors and alterations in signaling pathways are involved in primary and secondary resistance to immune checkpoints blockade. Improved identification of intrinsic and extrinsic factors and mechanisms of resistance or response to immune checkpoints blockade may not only provide novel prognostic or predictive biomarkers but also guide the optimal combination/sequencing of immune checkpoint blockade therapy in the clinic. Here, we review the underlying biology and role of immune checkpoints blockade in patients with MM. Furthermore, we review the host and tumor-related factor effects on immune checkpoints blockade in MM immunotherapy.