Brazilian family with pure autosomal dominant spastic paraplegia maps to 8q: Analysis of muscle beta 1 syntrophin

Abstract

The autosomal dominant hereditary spastic paraplegias (AD-HSP) are a heterogeneous group of degenerative disorders of the central motor system, characterized by progressive spasticity of the lower limbs. Five loci for pure AD-HSP have been identified to date: SPG3 at 14q, SPG4 at 2p, SPG6 at 15q, SPG8 at 8q, and more recently SPG10 at 12q. We have analyzed a Brazilian family with 16 affected individuals by pure AD-HSP who developed progressive gait disturbance with onset at age 18-26 years. Linkage analysis performed with 13 relatives (6 affected and 7 normal) excluded SPG3, SPG4, and SPG6 as candidate regions. However, positive LOD scores were obtained with markers flanking the candidate region for the SPG8 locus [maximum two point Lod score (Zmax) = 3.3 at theta = 0 for D8S1804]. In this region lies the syntrophin beta 1 gene (SNT2B1), a widely expressed dystrophin-associated protein and therefore a good positional and functional candidate for this disease. Immunohistochemical and Western Blot (WB) studies showed that the distribution, expression, and apparent molecular weight of the beta 1 syntrophin protein were comparable to those of normal control individuals. Therefore, it is unlikely that defects in this protein are related to SPG8, at least in the present family.

Hereditary spastic paraplegia: Clinical-genetic characteristics and evolving molecular mechanisms

“…KIAA0196 mutations, reported in a few families with pure HSP (de Bot et al, 2013;Rocco et al, 2000), lead to reduction of axonal outgrowth with a loss-of-function mechanism (Clemen et al, 2010) disrupting the endosome membrane trafficking (Freeman et al, 2013).…”

Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance

“…Clinical presentation: SPG8 is a pure SPG [68]. Some patients may present with distal wasting of the lower limbs, urinary urgency, or decreased vibration sense [68].…”

“…Clinical presentation: SPG8 is a pure SPG [68]. Some patients may present with distal wasting of the lower limbs, urinary urgency, or decreased vibration sense [68]. In single cases weakness may progress to such a degree that patients require a wheelchair [68].…”

Mutations in the KIAA0196 Gene at the SPG8 Locus Cause Hereditary Spastic Paraplegia

“…15 This family, as well as a third Brazilian family linked to SPG8, also presented with pure adult-onset HSP. 16 For two of the families, a muscle biopsy was performed 14,16 ; however, no gross histological or histochemical abnormalities were observed. Ragged red fibers have been observed in muscle biopsies of patients with HSP who have paraplegin mutations.…”

“…Genes were screened in an expanded candidate SPG8 locus defined by these four families, along with the British and Brazilian families described above. 15,16 This led to the identification of three point mutations in the KIAA0196 gene encoding the strumpellin protein product.…”