Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

X-linked hereditary spastic paraplegias (HSP) present with two distinct phenotypes, pure and complicated. The pure form is characterized by spasticity and gait difficulties but lacks the additional features (nystagmus, dysarthria, mental retardation) present in the complicated form. The complicated form is heterogeneous, caused by mutations of the L1CAM gene at Xq28 (SPG1) or the PLP gene at Xq22 (SPG2) that is allelic to Pelizaeus-Merzbacher disease (PMD). Since in one kindred (K313) the pure form of HSP was also mapped to Xq22, this raises the issue as to whether a pure form of HSP exists that is allelic to X-linked complicated HSP (SPG2) and PMD. To answer this question, we carried out linkage analysis in a new pedigree with pure HSP (K101) and refined linkage in pedigree K313. The PLP gene was also screened for mutation by direct sequencing and reverse-transcriptase polymerase chain reaction (RT-PCR). In both families, the disease locus mapped to Xq22 with Lod scores at zero recombination of 5.3 for COL4A5 2B6 in K313 and 2.4 for DXS101 in K101. A T to C transition in exon 5 of the PLP gene was identified from affected individuals of K313. This transition causes a Ser to Pro mutation in the major extracellular loop of PLP/DM20. This finding demonstrates that a form of X-linked pure spastic paraplegia, X-linked complicated HSP (SPG2) and PMD are allelic disorders. There was no evidence of mutations in either coding sequences or the intron/exon junctions of PLP in pedigree K101, suggesting that the disease-producing mutation may be in the noncoding portions of PLP or in a nearby gene.
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PMID:Refined genetic mapping and proteolipid protein mutation analysis in X-linked pure hereditary spastic paraplegia. 878 Jan 1

Familial spastic paraplegia (FSP or SPG) is a genetically heterogeneous group of upper motor neuron syndromes. To date, two distinct loci for X-linked recessive type (SPG1 and SPG2), three loci for autosomal dominant type (FSP1, FSP2 and FSP3), and one locus for autosomal recessive type have been reported. SPG1 and SPG2 have been mapped to Xq28 and Xq21-q22, respectively. SPG1 shows a mutation in the gene for neural cell adhesion molecule L1 (LICAM), which is an axonal glycoprotein involved in neuronal migration and differentiation. Different mutations of the same L1 gene also cause. MASA (mental retardation, aphasia, spastic paraplegia, adducted thumbs) syndrome and X-linked hydrocephalus. SPG2 shows mutations in one of the major myelin proteins, the proteolipid protein (PLP) gene, and is allelic to Pelizaeus-Merzbacher disease. Thus, mutations in two functionally distinct genes manifest the phenotype of X-linked spastic paraparesis. Three dominantly inherited spastic paraplegia genes have been genetically mapped to regions of chromosomes, yet no specific genes or mutations have been identified. FSP1 is mapped to a region of 7 cM on chromosome 14q12-q23 (approximately 20% of dominant FSP families) and FSP2 to 4 cM on chromosome 2p21-p24 (approximately 70% of dominant FSP families). Anticipation (increasing clinical severity in successive generations) has been observed in both FSP1 and FSP2 families. Another autosomal dominant FSP (FSP3) has been mapped in the centromeric region of chromosome 15q (< 10% of dominant FSP families). An autosomal recessive FSP has been mapped to chromosome 8q. The definite genetic heterogeneity in FSP indicates that a multitude of genes/proteins can cause spastic paraplegia. Clinical features of each of the loci which may permit differential diagnosis are discussed. We also present pedigrees of two new FSP families.
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PMID:Molecular genetics of familial spastic paraplegia: a multitude of responsible genes. 878 67

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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PMID:Further evidence for a fourth gene causing X-linked pure spastic paraplegia. 1221 Mar 42