The gene product of SS18L1, also known as CREST, has been associated with an amyotrophic lateral sclerosis (ALS)-like phenotype in patients with and without ALS. While many familial ALS genes are known, de novo mutations can also cause ALS-type phenotypes, known as sporadic ALS (SALS). When looking for de novo mutations in SALS patients, two mutations were found in SS18L1. In human cell culture, SS18L1 forms aggregates within nuclei, associates with human FUS, and disrupts paraspeckles (nuclear RNA granules often affected in neurodegenerative disease), all phenotypes associated with ALS.
There is a single moderate-ranking ortholog of human Hsap\SS18L1 in Drosophila, CG10555, for which RNAi targeting constructs and an insertion line have been generated.
The human gene Hsap\SS18L1 has been introduced into flies, both as wild-type (Hsap\SS18L1UAS.cKa) and two disease-associated mutations, SS18L1:p.Ile123Met and SS18L1:p.Gln388Ter . Expression of either wild-type or mutant Hsap\SS18L1 causes degeneration of the fly retina and a rough eye phenotype.
See also the reports on 'amyotrophic lateral sclerosis' (FBhh0000002) and the FUS-specific subtype 'amyotrophic lateral sclerosis 6' (FBhh0000018).
[updated November 2019 by FlyBase; FBrf0222196]
Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996, pubmed:8875253). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. [from MIM:105400, 2015.02.11]
CREST-deficient mice display defective dendritic branching, motor disturbances, and early lethality. (Aizawa et al. 2004, pubmed: 14716005.)
Although ~10% of cases have a family history of ALS (FALS), the majority of cases are sporadic (SALS). There have been significant inroads made into understanding SALS etiology, and now genetic contributors for ~11% of SALS cases are known. Since it is likely that genetics plays a central role in this form of the disease, there is intense interest in defining additional genetic causes and risk factors for SALS. (Chesi et al. 2013 and references therein, pubmed:23708140.)
Chesi et al. 2013 (pubmed:23708140) identified two de novo mutations when searching for causative genes of sporadic ALS. In a Caucasian woman with ALS, Chesi et al. identified a de novo heterozygous C-to-T transition in the SS18L1 gene, resulting in a gln388-to-ter (Q388X) substitution. The truncated protein lacks the last 9 amino acids that interact with CBP (600140). In a proband of UK ancestry with ALS, Chesi et al. identified a de novo heterozygous mutation in the SS18L1 gene, resulting in an ile123-to-met (I123M) substitution. [from MIM:606472, 2019.11.01]
CREST is prone to aggregation and co-aggregates with FUS but not with other two ALS-linked proteins, TDP-43 and TAF15, in cultured cells. Aggregation of CREST affects paraspeckle integrity, probably by trapping other paraspeckle proteins within aggregates. Like several other ALS-associated proteins, CREST is recruited to induced stress granules. Both wild-type protein and its mutants negatively affect neurite
network complexity of unstimulated cultured neurons when overexpressed. (Kukharsky et al. 2015, FBrf0243689.)
SS18L1 (also called CREST) is expressed only in post mitotic neurons and encodes an essential subunit of a neuron-specific chromatin-remodeling complex (nBAF) that resembles yeast SWI/SNF and SWR complexes. (Chesi et al. 2013 and references therein, pubmed:23708140.)
