This report describes neuronal ceroid lipofuscinosis 4 (NCL4 or CLN4), which shows autosomal dominant inheritance. The human gene implicated in this disease is DNAJC5, also known as CSPα, a secretory vesicle protein which acts as a chaperone at synapses. There is a single high-ranking ortholog of DNAJC5 in Drosophila, Csp. Many alleles have been generated of Csp, including amorphs, heat-sensitive loss-of-function alleles, and alleles carrying RNAi targeting constructs.
The human gene Hsap\DNAJC5 been introduced into flies, both as wild-type and as two disease-associated variants; see the 'Disease-Implicated Variants' table below. When expressed in flies, wild-type Hsap\DNAJC5 can be correctly palmitoylated and targeted to secretory vesicles, and can functionally complement (heterologously rescue) the premature lethality phenotype of a Csp deletion mutant. Expression of Hsap\DNAJC5 with NCL4-associated mutations in Drosophila results in heavy, SDS-resistant Hsap\DNAJC5 oligomers and endomembrane abnormalities, severely reducing viability.
Expressing Drosophila Csp with analogous mutations (see the 'Disease-Implicated Variants' table below) results in phenotypes similar to those of Hsap\DNAJC5 mutants.
[updated Feb. 2022 by FlyBase; FBrf0222196]
The neuronal ceroid lipofuscinoses (NCLs or CLNs) are a clinically heterogeneous group of neurodegenerative disorders; the general clinical course includes progressive dementia, seizures, and progressive visual failure (Mole et al., 2005; pubmed:15965709). [from MIM:256730; 2016.01.05]
Individuals with all forms NCL have shortened life expectancy, but it is highly variable, depending upon the form of the disease (from Medscape, http://emedicine.medscape.com/article/1178391-overview; 2016.01.05).
The term Batten disease may refer specifically to the juvenile-onset form, but is also used to refer to any NCL.
[CEROID LIPOFUSCINOSIS, NEURONAL, 4 (KUFS TYPE); CLN4](https://omim.org/entry/162350)
[DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 5; DNAJC5](https://omim.org/entry/611203)
Mutations in DNAJC5 cause autosomal dominant adult onset neuronal ceroid lipofusinosis (ANCL), an accumulation of autofluorescent lysosomal waste (known as lipofuscin) that causes a progressive neurodegenerative disorder characterized by ataxia, seizures and dementia. (From Zarouchlioti et al. 2018 and references therein, pubmed:29203718.)
Neuronal ceroid lipofuscinosis-4B is an autosomal dominant neurodegenerative disorder characterized by onset of symptoms in adulthood. It belongs to a group of progressive neurodegenerative diseases characterized by accumulation of intracellular autofluorescent lipopigment storage material in the brain and other tissues. Several different forms have been described according to age of onset (see, e.g., CLN3, MIM:204200). Individuals with the adult form, sometimes referred to as Kufs disease, develop psychiatric manifestations, seizures, cerebellar ataxia, and cognitive decline. (Summary by Benitez et al. 2011, pubmed:22073189, and Velinov et al. 2012, pubmed:22235333). [from MIM:162350, 2020.01.30]
CLN4 is caused by either the amino acid (aa) substitution L115R or the single amino acid deletion L116Δ in the SV protein CSPα, which is encoded by the human DNAJC5 gene. (From Imler et al. 2019, FBrf0244298.)
DNAJC5 mutations accounted for 38% of cases with unexplained adult-onset NCL in their cohort, with the mutations occurring at mutational hotspots. [from MIM:162350, 2020.01.30]
The location of the disease-associated mutations in the cysteine-rich region suggests a pathological defect in the membrane trafficking of DNAJC5 and subsequent protein aggregation. (From Zarouchlioti et al. 2018 and references therein, pubmed:29203718.)
DNAJC5 is a secretory vesicle protein found in both neuronal and non-neuronal tissues; however, the main α-isoform is only expressed in the brain. DNAJC5 has a role in binding and folding many proteins required at the synapse, such as SNAP-25, syntaxins and synaptotagmins, where it acts as a co-chaperone with the constitutive HSP70, HSC70 (HSPA8). DNAJC5, therefore, most likely plays a key role at the synapse as a chaperone. (From Zarouchlioti et al. 2018 and references therein, pubmed:29203718.)
One to one: 1 human gene to 1 Drosophila gene.
Single, high-ranking ortholog of human DNAJC5.
