Sequence Alterations within CYP7B1 Implicate Defective Cholesterol Homeostasis in Motor-Neuron Degeneration

Tsaousidou, Maria; Ouahchi, Karim; Warner, Thomas T.; Yang, Yi; Simpson, Michael A.; Laing, Nigel G.; Wilkinson, Philip A.; Madrid, R. E.; Patel, Harshad B.; Hentati, Fayçal; Patton, Michael A.; Hentati, Afif; Lamont, Philippa; Siddique, Teepu; Crosby, Andrew H.

doi:10.1016/j.ajhg.2007.10.001

Cited by 165 publications

(98 citation statements)

References 33 publications

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“…This was the case for SPG7 (paraplegin) and SPG5 (CYB7B1). 16,17,22,23 In terms of disease progression, SPG30 differs from other ARHSPs, such as SPG11, 24 in having a less severe evolution, as all affected members were still able to walk after disease durations of between 9 and 22 years even if maximal walking distance was reduced in all patients.…”

Section: Spg30 Phenotypementioning

confidence: 95%

KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations

et al. 2012

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The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. The nosology of autosomal recessive forms is complex as most mapped loci have been identified in only one or a few families and account for only a small percentage of patients. We used next-generation sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 in two patients from the original linked family. In addition, wide genome scan and candidate gene analysis were performed in a second family of Palestinian origin. We identified a single homozygous mutation, p.R350G, that was found to cosegregate with the disease in the SPG30 kindred and was absent in 970 control chromosomes while affecting a strongly conserved amino acid at the end of the motor domain of KIF1A. Homozygosity and linkage mapping followed by mutation screening of KIF1A allowed us to identify a second mutation, p.A255V, in the second family. Comparison of the clinical features with the nature of the mutations of all reported KIF1A families, including those reported recently with hereditary sensory and autonomic neuropathy, suggests phenotypegenotype correlations that may help to understand the mechanisms involved in motor neuron degeneration. We have shown that mutations in the KIF1A gene are responsible for SPG30 in two autosomal recessive HSP families. In published families, the nature of the KIF1A mutations seems to be of good predictor of the underlying phenotype and vice versa. INTRODUCTIONThe hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. 1 The mode of inheritance may be autosomal dominant, autosomal recessive (ARHSP) or X-linked. More than 48 different loci (SPGn) have been mapped so far, and 23 responsible genes identified. The corresponding proteins are often involved in intracellular trafficking or mitochondrial functions. 2,3 Clinically, one can distinguish between pure and complicated forms of HSP. 1,2 Pure forms consist of isolated pyramidal signs, such as spasticity, abnormal reflexes (brisk reflexes and Babinski sign) and motor deficit, often associated with sphincter disturbances and deep sensory loss. In the complicated forms of HSP the disease is variably associated with numerous combinations of neurological and extraneurological signs, such as cerebellar ataxia, dysarthria, mental retardation, peripheral neuropathy, optic atrophy, retinitis pigmentosa and/or hearing loss, which may be accompanied by abnormal brain MRI (atrophy of the cortex, cerebellum or corpus callosum, white matter abnormalities, etc).Mutations in the KIF1A gene (MIM 601255) were very recently described in two different clinically and genetically heterogeneous groups of neurodegenerative diseases. 4,5 In hereditary sensory and autonomic neuropathy (HSAN), all patients from four families with different origins shared a common hom...

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Section: Spg30 Phenotypementioning

confidence: 95%

KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations

et al. 2012

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“…The proband had definite HSP with disease onset at the age of seven, and some sensory involvement and seizures. A homozygous c.1450G>A mutation was previously reported in a Tunisian consanguineous family 2 and as a compound heterozygous state in a French sporadic case 4 . The second case was an unrelated French Canadian family (Figure, Family B), both the HSP proband and her affected brother had compound heterozygous mutations in CYP7B1.…”

Section: Resultsmentioning

confidence: 99%

“…Many HSP families have been mapped to this particular locus and the causative gene was finally identified in 2008. Mutations in Cytochrome P450, family 7, subfamily B polypeptide 1 (CYP7B1) gene were then found to underlie this particular disorder; homozygous mutations were originally identified in a consanguineous English family 2 . CYP7B1 extends over~220 Kb gene and contain six exons that encode for an evolutionarily conserved steroid metabolizing enzyme, cytochrome P450.…”

mentioning

confidence: 99%

CYP7B1 Mutations in French-Canadian Hereditary Spastic Paraplegia Subjects

Noreau

Szuto²,

Levert³

et al. 2012

Can. J. Neurol. Sci.

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“…This enzyme has been associated with several physiological processes, including brain function, immune system, cholesterol homeostasis and cellular viability and growth. Scientific publications in various areas have linked altered CYP7B1 levels and/or function to neurodegenerative processes, arthritis, and prostate cancer (Dulos et al, 2004;Olsson et al, 2007;Tsaousidou et al, 2008;Yau et al, 2003). However, the manner in which CYP7B1 affects these processes are in many cases unclear.…”

Section: Actions Of Cyp7b1 -Potential Role(s) For the Levels And Effementioning

confidence: 99%

Tissue-Specific Regulation of Sex Hormone Biosynthesis and Metabolism: Novel Aspects on Hormonal Signalling and Maintenance of Cellular Steroid Levels

Norlin¹,

Wikvall²

2012

Sex Hormones

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Sequence Alterations within CYP7B1 Implicate Defective Cholesterol Homeostasis in Motor-Neuron Degeneration

Cited by 165 publications

References 33 publications

KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations

KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations

CYP7B1 Mutations in French-Canadian Hereditary Spastic Paraplegia Subjects

Tissue-Specific Regulation of Sex Hormone Biosynthesis and Metabolism: Novel Aspects on Hormonal Signalling and Maintenance of Cellular Steroid Levels

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