Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia

Fard, Mohammad Ali Farazi; Rebelo, Adriana P.; Buglo, Elena; Nemati, Hamid; Dastsooz, Hassan; Gehweiler, Ina; Reich, Selina; Reichbauer, Jennifer; Quintáns, Beatriz; Ordóñez-Ugalde, Andrés; Cortese, Andrea; Courel, Steve; Abreu, Lisa; Powell, Eric; Danzi, Matt C.; Martuscelli, Nicole Belliard; Bis-Brewer, Dana M.; Tao, Feifei; Zarei, Fariba; Habibzadeh, Parham; Yavarian, Majid; Modarresi, Farzaneh; Silawi, Mohammad; Tabatabaei, Zahra; Yousefi, Masoume; Farpour, Hamid Reza; Keßler, Christoph; Mangold, Elisabeth; Kobeleva, Xenia; Tournev, Ivailo; Chamova, Teodora; Mueller, Amelie J.; Haack, Tobias B.; Tarnopolsky, Mark A.; Gan‐Or, Ziv; Rouleau, Guy A.; Synofzik, Matthis; Sobrido, María Jesús; Jordanova, Albena; Schüle, Rebecca; Züchner, Stephan; Faghihi, Mohammad Ali

doi:10.1016/j.ajhg.2019.05.009

Cited by 12 publications

(24 citation statements)

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“…mRNA studies demonstrated an escape of NMD for the recurrent frameshift variant, predicting the generation of a truncated protein. Our current study supports the recent publication on truncating variants in UBPA1 causing HSP (Farazi Fard et al, ), further delineating UBAP1 as an HSP‐causing gene. Overall, UBAP1 ‐HSP is characterized as a “pure” HSP that is typical of childhood‐onset and should be considered in the differential diagnosis when evaluating children who present with progressive spastic gait, and with no associated symptoms affecting the nervous system except the corticospinal tract.…”

Section: Discussionsupporting

confidence: 91%

“…We report frameshift UBAP1 variants in five individuals with childhood‐onset AD HSP. While preparing this manuscript, an article describing truncating variants in UBPA1 causing HSP was published (Farazi Fard et al, ), with eight different truncating mutations from 10 families, including a recurrent de novo c.426_427delGA variant in two families, which is identical to the variant in Families 1–4 reported here (Table ). Therefore, with our patients, there are now six HSP families with the c.426_427delGA variant identified, providing additional evidence for a mutational hotspot in UBAP1 .…”

Section: Discussionmentioning

confidence: 96%

“…In this study, through exome sequencing and interinstitutional data sharing, we identified ubiquitin‐associated protein 1 ( UBAP1 , MIM# 609787) as a novel disease‐causing gene for AD childhood‐onset nonsyndromic HSP in five unrelated families. Recently, truncating mutations in UBAP1 were reported in multiple families with similar phenotypes of SPG (Farazi Fard et al, ). The finding of de novo or disease‐segregating UBAP1 truncating variants in additional families independently strengthens the gene‐disease association and functional studies reported here support the dominant‐negative disease mechanism.…”

Section: Introductionmentioning

confidence: 98%

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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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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 98%

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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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“…Due to the rapid rate of progress of HSP research, new genes are being identified on a regular basis. Examples of recently identified HSP genes include UCHL1 (SPG79), UBAP1 (SPG80), SELENOI (SPG81), PCYT2 (SPG82), HPDL (SPG83), and those not yet assigned a locus (RNF170 and FAR1) [7][8][9][10][11][12][13][14][15][16]. Some genes are much rarer than others, and it cannot be excluded that certain mutations may be 'private' to individual families.…”

Section: Multiple Genes and A Rapidly Increasing Gene Listmentioning

confidence: 99%

Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

Saputra¹,

Kumar

2021

Curr Neurol Neurosci Rep

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Purpose of Review The hereditary spastic paraplegias (HSPs) are a group of disorders characterised by progressive lower limb weakness and spasticity. We address the challenges and controversies involved in the genetic diagnosis of HSP. Recent Findings There is a large and rapidly expanding list of genes implicated in HSP, making it difficult to keep gene testing panels updated. There is also a high degree of phenotypic overlap between HSP and other disorders, leading to problems in choosing the right panel to analyse. We discuss genetic testing strategies for overcoming these diagnostic hurdles, including the use of targeted sequencing gene panels, whole-exome sequencing and whole-genome sequencing. Personalised treatments for HSP are on the horizon, and a genetic diagnosis may hold the key to access these treatments. Summary Developing strategies to overcome the challenges and controversies in HSP may hold the key to a rapid and accurate genetic diagnosis.

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“…Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by slowly progressive spasticity and weakness of the lower extremities with or without other neurological system involvement. Currently, more than 80 different loci and 67 genes have been shown to be associated with HSP 1‐3 . Spastic paraplegia type 5 (SPG5) is an autosomal recessive (AR) subtype of HSP and caused by mutations in the CYP7B1 gene, which encodes the cytochrome P450 oxysterol 7a‐hydroxylase (CYP7B1) 4 .…”

Section: Introductionmentioning

confidence: 99%

Clinical characteristics of Taiwanese patients with Hereditary spastic paraplegia type 5

Chou

Soong

Lin

et al. 2020

Ann Clin Transl Neurol

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Objectives: To investigate the clinical, electrophysiological, neuroimaging characteristics and genetic features of SPG5 in Taiwan. Methods: Mutational analysis of the coding regions of CYP7B1 was performed by utilizing targeted resequencing analysis of the 187 unrelated Taiwanese HSP patients. The diagnosis of SPG5 was ascertained by the presence of biallelic CYP7B1 mutations. The SPG5 patients received clinical, electrophysiological, and neuroimaging evaluations. Disease severity was assessed by using the Spastic Paraplegia Rating Scale (SPRS) and the disability score. Two microsatellite markers as well as 18 singlenucleotide polymorphism (SNP) markers flanking CYP7B1 were genotyped to assess the founder effect of the CYP7B1 p.R112* mutation. Results: Nineteen SPG5 patients from 17 families were identified. They typically presented an insidious onset progressive spastic paraparesis with proprioception involvement beginning at age 8 to 40 years. Their MRIs often showed white matter abnormalities in bilateral occipito-parietal regions, spinal cord atrophy, and mild cerebellar atrophy. Six different mutations in CYP7B1 were recognized, including three novel ones (p.N131Ifs*4, p.A295V, and p.L439R). CYP7B1 p.R112* was the most common mutation and present in 88.2% of the 17 SPG5 pedigrees. The patients with homozygous CYP7B1 p.R112* mutations had a milder clinical severity. Detailed haplotype analyses demonstrated a shared haplotype in the 25 individuals carrying at least one single allele of CYP7B1 p.R112*, suggesting a founder effect. Interpretation: This study delineates the distinct clinical and genetic features of SPG5 in Taiwan and provides useful information for the diagnosis and management of SPG5, especially in patients of Chinese descent. 486

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Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia

Cited by 12 publications

References 0 publications

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

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

Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

Clinical characteristics of Taiwanese patients with Hereditary spastic paraplegia type 5

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