This report describes spastic paraplegia 17 (SPG17), which is an autosomal dominant subtype of spastic paraplegia. The human gene implicated in this disease is BSCL2, which encodes a multi-pass transmembrane protein that localizes to the endoplasmic reticulum and is predicted to function in lipid droplet formation and/or metabolism. There is a single orthologous gene in Drosophila, Seipin, for which an amorphic allele and multiple RNAi targeting constructs have been generated. BSCL2 has been implicated in multiple diseases (see OMIM:606158). Many loss-of-function mutations of BSCL2 result in congenital generalized lipodystrophy, type 2 (see OMIM:269700 and FBhh0000447).
UAS constructs of the human gene Hsap\BSCL2 have been introduced into flies, including wild-type and a variant associated with SPG17. Heterologous rescue (functional complementation) has been observed: when expressed in fat body, the wild-type human gene rescues the lipid storage defect of an amorphic Dmel\Seipin mutation.
Variant(s) implicated in human disease tested (as transgenic human gene BSCL2): the S90L (S154L) variant form has been introduced into flies. When expressed in fat body, a human gene carrying the S90L variant has also been found to rescue the phenotypes of an amorphic Dmel\Seipin mutation. This lends support to the hypothesis that S90L is a gain-of-function mutation.
Larvae homozygous for an amorphic mutation of Seipin exhibit reduced lipid storage in fat bodies and ectopic lipid droplets in the salivary glands. Genetic interactions of candidate genes have been assessed based on modification of this phenotype. Multiple physical interactions have been reported; see below and in the Seipin gene report.
[updated Jul. 2017 by FlyBase; FBrf0222196]
The hereditary spastic paraplegias (SPG, HSP) are a large group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity and weakness. SPG is classified by mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and whether the primary symptoms occur in isolation ('uncomplicated SPG') or with other neurologic abnormalities ('complicated SPG'). [from OMIM:182600; 15.06.29]
[SPASTIC PARAPLEGIA 17, AUTOSOMAL DOMINANT; SPG17](https://omim.org/entry/270685)
[BSCL2 GENE; BSCL2](https://omim.org/entry/606158)
See general description of spastic paraplegia, above.
The first sign of Silver syndrome is usually weakness in the muscles of the hands. These muscles amyotrophy, resulting in abnormal positioning of the thumbs and difficulty using the fingers and hands for tasks such as handwriting. People with Silver syndrome often have high-arched feet (pes cavus) and spasticity in the legs. The signs and symptoms of Silver syndrome typically begin in late childhood but can start anytime from early childhood to late adulthood. The muscle problems associated with Silver syndrome slowly worsen with age, but affected individuals can remain active throughout life. [from Genetics Home Reference, Silver syndrome; 2016.11.29]
One to one: 1 human to 1 Drosophila.