Hereditary spastic paraplegia

Blackstone, Craig

doi:10.1016/b978-0-444-64076-5.00041-7

Cited by 117 publications

(135 citation statements)

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“…3 Mutations in genes that encode these proteins have been implicated in a range of human disorders, including Alzheimer disease and hereditary spastic paraplegia (HSP), the latter of which has been studied extensively in connection with ER-shaping proteins. 4,5 For instance, heterozygous mutations in ATL1 (MIM: 606439), encoding Atlastin-1, cause autosomal-dominant spastic paraplegia 3A (SPG3A [MIM: 182600]) and are the second most common cause of HSP. [4][5][6] SPG12 (MIM: 604805), SPG31 (MIM: 610250), and SPG72 (MIM: 515626) are likewise associated with mutations in REEP1 (MIM: 609139), RTN2 (MIM: 603183), and REEP2 (MIM: 609347), respectively.…”

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confidence: 99%

Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome

Breuss

Nguyen

Song

et al. 2018

The American Journal of Human Genetics

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The dynamic shape of the endoplasmic reticulum (ER) is a reflection of its wide variety of critical cell biological functions. Consequently, perturbation of ER-shaping proteins can cause a range of human phenotypes. Here, we describe three affected children (from two consanguineous families) who carry homozygous loss-of-function mutations in LNPK (previously known as KIAA1715); this gene encodes lunapark, which is proposed to serve as a curvature-stabilizing protein within tubular three-way junctions of the ER. All individuals presented with severe psychomotor delay, intellectual disability, hypotonia, epilepsy, and corpus callosum hypoplasia, and two of three showed mild cerebellar hypoplasia and atrophy. Consistent with a proposed role in neurodevelopmental disease, LNPK was expressed during brain development in humans and mice and was present in neurite-like processes in differentiating human neural progenitor cells. Affected cells showed the absence of full-length lunapark, aberrant ER structures, and increased luminal mass density. Together, our results implicate the ER junction stabilizer lunapark in establishing the corpus callosum.

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confidence: 99%

Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome

Breuss

Nguyen

Song

et al. 2018

The American Journal of Human Genetics

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“…Proteins implicated in HSP are part of specific molecular pathways or functional modules when mutated, leading to degeneration or abnormal development of long spinal cord axons. One of the known disturbed pathways or functional modules involves endosome membrane trafficking, vesicle formation and selective uptake of proteins into vesicles (Blackstone, ; Fink, ; Lo Giudice et al, ). Several of the known HSP‐causing genes encode proteins function in this pathway, including AP4B1 associated AR SPG47 (MIM# 614066) (Abou Jamra et al, ), AP5Z1 associated AR SPG48 (MIM# 613647; Slabicki et al, ), AP4M1 associated AR SPG50 (MIM# 612936; Verkerk et al, ), AP4E1 associated AD SPG51 (MIM# 613744; Abou Jamra et al, ), AP4S1 associated AR SPG52 (MIM# 614067; Abou Jamra et al, ), and the above mentioned VPS37A associated AR SPG53.…”

Section: Discussionmentioning

confidence: 99%

“…Several of the known HSP‐causing genes encode proteins function in this pathway, including AP4B1 associated AR SPG47 (MIM# 614066) (Abou Jamra et al, ), AP5Z1 associated AR SPG48 (MIM# 613647; Slabicki et al, ), AP4M1 associated AR SPG50 (MIM# 612936; Verkerk et al, ), AP4E1 associated AD SPG51 (MIM# 613744; Abou Jamra et al, ), AP4S1 associated AR SPG52 (MIM# 614067; Abou Jamra et al, ), and the above mentioned VPS37A associated AR SPG53. In addition, proteins functioning in the ubiquitination machinery have also been associated with HSP (Bilguvar et al, ; Blackstone, ; Lo Giudice et al, ). Therefore, it is conceivable that deleterious variants in UBAP1 , which disturb its regular functions in endosomal trafficking and interaction with ubiquitinated proteins, could potentially cause HSP.…”

Section: Discussionmentioning

confidence: 99%

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Truncating variants in UBAP1 associated with childhood‐onset nonsyndromic hereditary spastic paraplegia

Chen

Rosenfeld

et al. 2019

Human Mutation

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Hereditary spastic paraplegia (HSP) is a group of disorders with predominant symptoms of lower-extremity weakness and spasticity. Despite the delineation of numerous genetic causes of HSP, a significant portion of individuals with HSP remain molecularly undiagnosed. Through exome sequencing, we identified five unrelated families with childhood-onset nonsyndromic HSP, all presenting with progressive spastic gait, leg clonus, and toe walking starting from 7 to 8 years old. A recurrent two-base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense-mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified in this study are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant-negative effect on the normal function of the endosome-specific endosomal sorting complexes required for the transport-I complex. K E Y W O R D S autosomal dominant, escape of nonsense-mediated decay, hereditary spastic paraplegia, UBAP1

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“…Recently, it has been reported that the HSPs exist not only in "pure" forms but also in "complex" forms that are linked with other neurologic and extra neurologic conditions. Moreover, the HSPs are among the most genetically diverse neurologic disorders, with well over 70 distinct genetic loci, for which about 60 mutated genes have already been identified (Blackstone, 2018). The diagnosis of HSP is based on the presence of a clinical history of progressive spastic paraparesis in a pure form or associated with other neurological and systemic manifestations (with or without familial history), evidence of a genetic mutation in a locus related to a phenotype of HSP previously described in the literature, and exclusion of structural disorders or other genetic or acquired conditions that explain the clinical picture (Sedel et al, 2007;De Bot et al, 2010;Lo Giudice et al, 2014;Klebe et al, 2015;Pedroso et al, 2015;Souza et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Exome Analysis Identified Novel Homozygous Splice Site Donor Alteration in NT5C2 Gene in a Saudi Family Associated With Spastic Diplegia Cerebral Palsy, Developmental Delay, and Intellectual Disability

et al. 2020

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Hereditary spastic paraplegias (HSPs) is a rare heterogeneous group of neurodegenerative diseases, with upper and lower limb spasticity motor neuron disintegration leading to paraplegias. NT5C2 gene (OMIM: 600417) encode a hydrolase enzyme 5'-nucleotidase, cytosolic II play an important role in maintaining the balance of purine nucleotides and free nucleobases in the spinal cord and brain. In this study we have identified a large consanguineous Saudi family segregating a novel homozygous splice site donor alteration in NT5C2 gene leading to spastic diplegia cerebral palsy, developmental delay and microcephaly. Whole exome sequencing (WES) was performed for the affected members of the family to study the novel mutation. WES data analysis, confirmed by Sanger sequencing analysis, identifies a homozygous splice site donor alteration of possible interest in NT5C2 (ENST00000343289: c.539+1G > T) at the sixth exon/intron boundaries. The mutation was further ruled out in 100 healthy control from normal population. The novel homozygous mutation observed in this study has not been reported in the literature or variant databases. The identified splicing alteration broadens the mutation spectrum of NT5C2 gene in neurodevelopmental disorders. To the best of our knowledge this is the first report from Saudi Arabia.

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Hereditary spastic paraplegia

Cited by 117 publications

References 110 publications

Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome

Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome

Truncating variants in UBAP1 associated with childhood‐onset nonsyndromic hereditary spastic paraplegia

Exome Analysis Identified Novel Homozygous Splice Site Donor Alteration in NT5C2 Gene in a Saudi Family Associated With Spastic Diplegia Cerebral Palsy, Developmental Delay, and Intellectual Disability

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