Fonksiyon kaybı DESI varyantları yeni bir ALS benzeri sendroma neden olmaktadır

Neurodegenerative diseases encompass a diverse group of disorders characterized by progressive and irreversible neuronal damage. Among them, amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, defined by progressive degeneration of upper and lower motor neurons. ALS has a multifactorial aetiology shaped by complex interaction between genetic and environmental factors, with about 20% of cases explained by monogenic causes. To date, pathogenic variants in more than 40 genes have been identified. Notably, several ALS-associated genes including SOD1, TARDBP as well as UBQLN family members, converge on proteostasis pathways, a major hallmark in ALS pathophysiology. Yet nearly 80% of patients still lack a molecular diagnosis, highlighting the critical need for continued genetic investigation. Through international collaboration, we identified seven patients from six unrelated families presenting with ALS-like phenotypes. Despite their diverse geographic origins, all individuals exhibited hallmark clinical features, most notably progressive weakness and combined involvement of upper and lower motor neurons. Whole-exome sequencing (WES) excluded pathogenic variants in known neuromuscular disease genes but revealed novel homozygous or compound heterozygous variants in Desumoylating Isopeptidase 1 (DESI1). These included three splice-site, two frameshift, and one nonsense mutations. All variants were extremely rare in the general population and segregated consistently with autosomal recessive inheritance. DESI1 encoding a protein with a conserved cysteine protease PPPDE domain and nuclear export signals (NES), acts as an adaptor for the nuclear export of UBQLN proteins. Previously not associated with human disease, DESI1 emerges as a novel ALS candidate linking nuclear transport defects to proteostasis disruption. To assess the functional consequences of these variants, we overexpressed DESI1 variants in HEK293T cells. Splicing and immunoblotting assays revealed truncated or aberrant proteins lacking essential domains, including the highly conserved catalytic cysteine residue and nuclear export signals. Western blot analysis showed that these proteins undergo rapid proteasomal degradation. Co-immunoprecipitation further revealed abnormal interactions with UBQLN4 and impaired deSUMOylase activity toward BZEL, the only known substrate. Preliminary analyses on patient-derived fibroblasts supported these findings, revealing impaired proteostasis. Together, these findings establish DESI1 as a novel ALS-associated gene and demonstrate that loss-of-function variants provide mechanistic insights linking its dysfunction to ALS pathogenesis.