How Genomics Drives Mechanistic Insight and Therapy for Jazelle Disease and CHAPLE Disease

The team found loss-of-function mutations in GMAP5 causing early-onset immunodeficiency in nine consanguineous families: T/B lymphopenia, liver disease, autoimmune antibodies, splenomegaly, named Jazelle disease; GMAP5 is a small GTPase localized to the lysosomal outer membrane.; Patients' T cells showed a senescence phenotype (elevated CD57, KLRG1; decreased CD27/CD28; high IL-6/IL-8 secretion); CRISPR knockout of GMAP5 in activated T cells caused necrosis and accumulation of long-chain ceramides, and fumonisin B1 blocking ceramide synthesis rescued survival.; Mechanistically, GMAP5 forms a complex with LCK and CK2; its loss leaves CK2 persistently bound to ceramide synthase causing ceramide excess, driven by TCR stimulation, and the CK2 inhibitor CX-4945 can prevent accumulation; the complex links to ragulator–mTOR, rapamycin alleviated senescence markers, and one patient's spleen and lymph nodes shrank after treatment (preliminary, pending verification).; The second disease is CD55 (decay-accelerating factor) deficiency: failure to inhibit complement C3 convertase leads to deposition of membrane attack complex (MAC) and anaphylatoxins on intestinal lymphatics; lymphatic dilation and rupture cause protein-losing enteropathy (low IgG, low albumin, thrombosis), named CHAPLE disease.

• The team found loss-of-function mutations in GMAP5 causing early-onset immunodeficiency in nine consanguineous families: T/B lymphopenia, liver disease, autoimmune antibodies, splenomegaly, named Jazelle disease; GMAP5 is a small GTPase localized to the lysosomal outer membrane.
• Patients' T cells showed a senescence phenotype (elevated CD57, KLRG1; decreased CD27/CD28; high IL-6/IL-8 secretion); CRISPR knockout of GMAP5 in activated T cells caused necrosis and accumulation of long-chain ceramides, and fumonisin B1 blocking ceramide synthesis rescued survival.
• Mechanistically, GMAP5 forms a complex with LCK and CK2; its loss leaves CK2 persistently bound to ceramide synthase causing ceramide excess, driven by TCR stimulation, and the CK2 inhibitor CX-4945 can prevent accumulation; the complex links to ragulator–mTOR, rapamycin alleviated senescence markers, and one patient's spleen and lymph nodes shrank after treatment (preliminary, pending verification).
• The second disease is CD55 (decay-accelerating factor) deficiency: failure to inhibit complement C3 convertase leads to deposition of membrane attack complex (MAC) and anaphylatoxins on intestinal lymphatics; lymphatic dilation and rupture cause protein-losing enteropathy (low IgG, low albumin, thrombosis), named CHAPLE disease.
• Treatment with the anti-C5 antibody eculizumab and Regeneron's pozelimab (a subcutaneously administered human C5-inhibiting antibody) restored patients' serum albumin, IgG, and vitamin B12 within weeks, with symptoms resolving; the FDA approved pozelimab last August as the first therapy for CHAPLE disease (as reported by the speaker, approved).
• Lenardo noted that his genomics project also led to another drug for APDS/PASLI disease approved by the FDA in 2023, emphasizing that gene identification can lead to mechanism-driven precision therapy.