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Mutations in L1-CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS.

ABSTRACT: The suggestion that the three X linked syndromes X linked spastic paraplegia (MIM 312900), MASA syndrome (MIM 303350), and X linked hydrocephalus owing to stenosis of the aqueduct of Sylvius (MIM 307000) are variable clinical manifestations of mutations at the same locus at Xq28 was confirmed by the finding of mutations in the L1-CAM gene in the three syndromes. Recently, two families in which different subjects showed a clearly different phenotype within the same family of the three X linked syndromes were described. A reverse transcription PCR assay was developed for the analysis of the L1-CAM cDNA in two of the members of these families. RNA isolated from EBV transformed cell lines and a colon carcinoma derived cell line was used as a starting material. The L1-CAM cDNA of two male patients from each family was sequenced. We report two new mutations in the L1-CAM gene in these two families showing that the three different phenotypes observed in different generations within the same family are variable phenotypic expressions of the same mutation.

SUBMITTER: Ruiz JC

PROVIDER: S-EPMC1050549 | biostudies-literature | 1995 Jul

REPOSITORIES: biostudies-literature

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Mutations in L1-CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS.

Ruiz J C JC Cuppens H H Legius E E Fryns J P JP Glover T T Marynen P P Cassiman J J JJ

Journal of medical genetics 19950701 7

The suggestion that the three X linked syndromes X linked spastic paraplegia (MIM 312900), MASA syndrome (MIM 303350), and X linked hydrocephalus owing to stenosis of the aqueduct of Sylvius (MIM 307000) are variable clinical manifestations of mutations at the same locus at Xq28 was confirmed by the finding of mutations in the L1-CAM gene in the three syndromes. Recently, two families in which different subjects showed a clearly different phenotype within the same family of the three X linked sy ...[more]

PMID: 7562969

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Project description:Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower-limb predominant spastic paraparesis. Cognitive impairment was present in most of the cases and ranged from very mild deficits to advanced dementia with fronto-temporal characteristics. Nerve conduction studies revealed involvement of the peripheral motor and sensory nerves. Only one of five patients with hereditary spastic paraplegia showed clinical indication of extrapyramidal involvement in the form of subtle bradykinesia and slight resting tremor. Neuroimaging cranial investigations revealed pronounced vermian and hemispheric cerebellar atrophy. Notably, reduced striatal dopamine was apparent in the brain of one of the patients, who had no clinical signs or symptoms of extrapyramidal involvement.

Dataset Information

Mutations in L1-CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS.

Publications

Mutations in L1-CAM in two families with X linked complicated spastic paraplegia, MASA syndrome, and HSAS.

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