| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10q22.1 | {Parkinson disease 24, autosomal dominant, susceptibility to} | 619491 | Autosomal dominant | 3 | PSAP | 176801 |
A number sign (#) is used with this entry because of evidence that susceptibility to autosomal dominant Parkinson disease-24 (PARK24) is conferred by heterozygous variation in the saposin D domain of the PSAP gene (176801) on chromosome 10q22.
Parkinson disease-24 (PARK24) is an autosomal dominant disorder characterized by classic Parkinson disease features, including adult onset, asymmetric limb involvement initially, and slowly progressive motor dysfunction. PARK24 shows incomplete penetrance, consistent with the presence of the PSAP mutation being a susceptibility factor for development of the disease (Oji et al., 2020).
For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see 168600.
Oji et al. (2020) reported 3 unrelated Japanese families segregating autosomal dominant adult-onset Parkinson disease. There were 8 affected individuals, 2 of whom had died without genetic material available for study. The remaining 6 patients presented between 33 and 60 years of age with classic features of the disorder, including asymmetric involvement at onset, resting tremor, and initial good response to dopaminergic therapy. There were 2 sibs in family 2 who carried the PSAP mutation and presented with extrapyramidal signs such as tremor and muscular rigidity, but they were not clearly diagnosed with Parkinson disease.
The transmission pattern of PARK24 in the families reported by Oji et al. (2020) was consistent with autosomal dominant inheritance.
In 6 affected patients from 3 unrelated Japanese families with PARK24, Oji et al. (2020) identified heterozygous mutations affecting the saposin D domain of the PSAP gene (176801.0016-176801.0018). The mutations, which were found by targeted direct Sanger sequencing, were either absent from or present at a low frequency in the gnomAD database. There was evidence of variable expressivity and incomplete penetrance. Patient-derived skin fibroblasts showed abnormal accumulation of autophagic vacuoles, suggesting lysosomal abnormalities. Patient-derived pluripotent stem cells induced into dopaminergic neurons showed impaired alpha-synuclein (SNCA; 163890) degradation compared to controls. PSAP was retained abnormally in the endoplasmic reticulum with a failure of processing in the Golgi apparatus. The findings suggested that mutation in the saposin D domain disrupted protein structure and caused defective intracellular trafficking. The report added to the growing recognition of the genetic involvement of lysosomal dysfunction in Parkinson disease.
Facchi et al. (2020) did not identify any pathogenic variants in the saposin D region of the PSAP gene among 400 Italian patients with familial Parkinson disease. The authors suggested that saposin D mutations are not a common cause of the disorder.
Sosero et al. (2020) did not find an association between variation in the PSAP gene and Parkinson disease among several large cohorts comprising 4,132 patients with Parkinson disease and 4,470 controls of western European descent.
Oji et al. (2020) found that mutant mice with a homozygous C509S mutation in the saposin D domain of the Psap gene, which is predicted to disrupt a disulfide bond, had progressive locomotor decline due to dopaminergic neurodegeneration in the brain. These abnormalities were associated with impaired lysosomal Psap trafficking and Psap-immunoreactive inclusions in the endoplasmic reticulum.
Facchi, D., Rimoldi, V., Straniero, L., Paraboschi, E. M., Solda, G., Zecchinelli, A. L., Cilia, R., Duga, S., Pezzoli, G., Asselta, R. Saposin D variants are not a common cause of familial Parkinson's disease among Italians. (Letter) Brain 143: e71, 2020. [PubMed: 32793950] [Full Text: https://doi.org/10.1093/brain/awaa213]
Oji, Y., Hatano, T., Ueno, S.-I., Funayama, M., Ishikawa, K., Okuzumi, A., Noda, S., Sato, S., Satake, W., Toda, T., Li, Y., Hino-Taki, T., and 20 others. Variants in saposin D domain of prosaposin gene linked to Parkinson's disease. Brain 143: 1190-1205, 2020. [PubMed: 32201884] [Full Text: https://doi.org/10.1093/brain/awaa064]
Sosero, Y. L., Bandres-Ciga, S., Hassin-Baer, S., Alcalay, R. N., Gan-Or, Z. Lack of evidence for genetic association of saposins A, B, C and D with Parkinson's disease. (Letter) Brain 143: e72, 2020. [PubMed: 32793944] [Full Text: https://doi.org/10.1093/brain/awaa214]