Evidence of a third locus in X-linked recessive spastic paraplegia

Steinmüller, Rolf; Lantigua-Cruz, A.; Garcia-Garcia, R.; Kostrzewa, Markus; Steinberger, Daniela; Müller, Ulrich

doi:10.1007/s004390050507

Cited by 39 publications

(13 citation statements)

References 8 publications

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“…However X-linked (SPG16, Steinmuller et al 1997) and autosomal recessive (SPG5, 24, 28) uncomplicated forms also occur (Hentati et al 1994;Hodgkinson et al 2002;Bouslam et al 2005). Ten loci for autosomal dominant "uncomplicated"/"pure" hereditary spastic paraplegia (ADPHSP) have been mapped, for eight of which the causative genes have been identiWed (OMIM): SPG3A (MN_606439; 14q11-q21; Atlastin), SPG4 (MN_604277; 2p22; Spastin), SPG6 (MN_ 600303; 15q11.1; NIPA1), SPG8 (MN_603563; 8q23-q24; KIAA0196), SPG10 (MN_604187; 12q13; KIF5A), SPG12 (MN_604805; 19q13), SPG13 (MN_605280; 2q24-34; Chaperonin 60), SPG19 (MN_607152; 9q33-34), SPG31 (MN_609139; 2p12; REEP1) and SPG33 (MN_610243, 10q24.2; ZFYVE27).…”

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confidence: 97%

A novel locus for autosomal dominant “uncomplicated” hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3

et al. 2007

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Hereditary spastic paraplegias (HSPs) are genetically and phenotypically heterogeneous. Both "uncomplicated" and "complicated" forms have been described, with autosomal dominant, autosomal recessive, and X-linked inheritance. Hitherto, ten autosomal dominant "uncomplicated" HSP (ADHSP) loci have been mapped. Here, we report linkage of ADHSP with markers of the 8p21.1-q13.3 chromosomal region in a large French family, including 29 examined at-risk individuals. The age at onset varied from 8 to 60 years with a mean of 31.6 +/- 16.4 years. Multipoint and two-point LOD-score calculations as well as haplotype reconstruction in this region gave support to the location of this novel ADHSP locus (SPG37) in a 43.5 cM genetic interval flanked by loci D8S1839 and D8S1795. The region was shared by all definitely (n = 13), probably (n = 3) and possibly (n = 2) affected patients with a maximum LOD score of 4.20 at the D8S601 locus. Two candidate genes, encoding the kinesin family member 13B and neuregulin 1 (isoforms SMDF and GFF2), were screened for mutations, but no disease-causing alterations were identified. Interestingly, another region, on chromosome 10q22.3-23.31, was found to segregate in all affected patients (but not in probably or possibly affected subjects) and in a high proportion of healthy at risk individuals, suggesting that this locus might act as a modifier of the phenotype.

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confidence: 97%

A novel locus for autosomal dominant “uncomplicated” hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3

et al. 2007

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“…The present family, as well as the pedigree K101 reported previously [Cambi et al, 1995], has a mild form of pure X-linked spastic paraplegia. However, the other two families [Lazzarini et al, 1997;Steinmü ller et al, 1997] have a severe complicated clinical picture. It will be interesting to know if these phenotypes may also represent allelic forms of the same gene(s) or if they are caused by nonallelic genetic heterogeneity.…”

Section: Discussionmentioning

confidence: 98%

“…A mutation in the PLP gene was found by Cambi et al [1996] in a family with pure X-linked spastic paraplegia, confirming that mutations in this gene may cause both pure and complicated forms. A third locus, more than 10 cM away from the PLP gene, was identified in a family with PelizaeusMerzbacher-like disease, but the gene product is still unknown [Lazzarini et al, 1997;Steinmü ller et al, 1997;Claes et al, 2000].…”

Section: Introductionmentioning

confidence: 98%

Further evidence for a fourth gene causing X‐linked pure spastic paraplegia

et al. 2002

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X-linked hereditary spastic paraplegias (HSPs) present with two distinct phenotypes: pure and complicated. The pure form is characterized by slowly progressive weakness and spasticity of the lower limbs, whereas the complicated forms have additional features (optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, epilepsy, ataxia, ichthyosis, mental retardation, and deafness). Three X-linked loci have been identified for the complicated HSP, while mutations in the proteolipid gene (PLP) (locus SPG2) were implicated in both pure and complicated forms. The absence of identified mutations in the PLP gene in families with both complicated and pure HSP, linked to the SPG2 locus, suggests the existence of another gene in close proximity. We had previously reported a large pedigree with an X-linked form of pure HSP affecting 24 males [Zatz et al., 1976: J Med Genet 13:217-222]. Here, we present the results of linkage analysis in 19 members of this Brazilian family with markers in or near the PLP locus. Positive LOD scores were obtained with markers at the PLP locus (Zmax = 2.41 at Theta = 0); however, no mutation was found in the coding region of PLP, the intron-exon boundaries, or part of the promoter region. The possibility of a duplication of the PLP gene was also excluded. These results suggest either that there is another X-linked gene in close proximity to the PLP gene or that a novel mutation in the noncoding regions of the PLP gene may cause the disease in this family.

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“…Recently, Steinmuller et al [1997] mapped a third X-linked SPG locus at Xq11.2-q23 in a family with the complicated form of the disorder. In the family that we studied, SPG is thought to have been caused by a breakpoint in Xq11.2 arising from rDNA insertion.…”

Section: Discussionmentioning

confidence: 99%

“…The gene of Xq28 codes for mutations in the L1 cell adhesion molecule gene in SPG1, whereas defects in the proteolipid protein (PLP) gene in Xq21 have been identified in SPG2 [Kobayashi et al, 1996]. In addition, recent studies have suggested the existence of a third gene locus for X-linked SPG, in a more proximal, pericentromeric region on the long arm of the X chromosome [Steinmuller et al, 1997]. We describe a family with pure SPG, lacking nystagmus or mental retardation, and characterized by rDNA insertion in Xq11.2.…”

Section: Introductionmentioning

confidence: 98%

Segregation of a pure form of spastic paraplegia and NOR insertion into Xq11.2

Tamagaki¹,

Shima

Tomita³

et al. 2000

Am. J. Med. Genet.

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A 3-year-old boy, his 7-year-old brother, and a maternal uncle had a pure form of spastic paraplegia and a variant X chromosome with a faintly stained gap at Xq11.2. The mother of the propositus also had the variant X chromosome but was clinically unaffected. Three other unaffected females in the family did not have the variant X chromosome. The gaps in the variant X chromosome from the affected members and the mother were Ag-NOR staining positive, C-banding negative, rDNA FISH analysis positive, and alpha-satellite FISH analysis negative. The gap, therefore, represented an insertion of the nucleolus organizer region (NOR) derived from the short arm of an acrocentric chromosome. The variant X chromosome of the mother was randomly inactivated, as evidenced by BrdU replication analysis of her Epstein-Barr virus-transformed lymphoblastoid cells. Because mutations of the proteolipid protein gene at Xq21 have been responsible for a pure form of spastic paraplegia, this was also investigated but found to be negative in all affected relatives. Summing up these findings, it is proposed that the NOR insertion in the affected members of the family disrupted a hitherto unknown gene for a pure form of spastic paraplegia, situated at Xq11.2, and caused the disorder.

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Evidence of a third locus in X-linked recessive spastic paraplegia

Cited by 39 publications

References 8 publications

A novel locus for autosomal dominant “uncomplicated” hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3

A novel locus for autosomal dominant “uncomplicated” hereditary spastic paraplegia maps to chromosome 8p21.1-q13.3

Further evidence for a fourth gene causing X‐linked pure spastic paraplegia

Segregation of a pure form of spastic paraplegia and NOR insertion into Xq11.2

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