Analysis of the GCG repeat length in NIPA1 gene in C9orf72-mediated ALS in a large Italian ALS cohort

Corrado, Lucia; Brunetti, Maura; Pierro, Alice Di; Barberis, Marco; Croce, Roberta; Bersano, Enrica; Marchi, Fabiola De; Zuccalà, Miriam; Barizzone, Nadia; Calvo, Andrea; Moglia, Cristina; Mazzini, Letizia; Chiò, Adriano; D’Alfonso, Sandra

doi:10.1007/s10072-019-04001-3

Cited by 8 publications

(9 citation statements)

References 7 publications

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“…However, the results do not boast a common conclusion: the study performed by Dekker et al (2016) claimed to have found a high frequency of NIPA1 REs in C9orf72-sALS cases, hypothesizing their role in modifying the C9orf72 phenotype [36]. The study by Corrado et al [37], consistent with the other two papers [34,38], concluded that the length of the NIPA1 allele does not appear to affect the clinical features of C9orf72 carriers.…”

Section: Discussionmentioning

confidence: 87%

Investigating Repeat Expansions in NIPA1, NOP56, and NOTCH2NLC Genes: A Closer Look at Amyotrophic Lateral Sclerosis Patients from Southern Italy

Ruffo,

De Amicis,

La Bella

et al. 2024

Cells

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The discovery of hexanucleotide repeats expansion (RE) in Chromosome 9 Open Reading frame 72 (C9orf72) as the major genetic cause of amyotrophic lateral sclerosis (ALS) and the association between intermediate repeats in Ataxin-2 (ATXN2) with the disorder suggest that repetitive sequences in the human genome play a significant role in ALS pathophysiology. Investigating the frequency of repeat expansions in ALS in different populations and ethnic groups is therefore of great importance. Based on these premises, this study aimed to define the frequency of REs in the NIPA1, NOP56, and NOTCH2NLC genes and the possible associations between phenotypes and the size of REs in the Italian population. Using repeat-primed-PCR and PCR-fragment analyses, we screened 302 El-Escorial-diagnosed ALS patients and compared the RE distribution to 167 age-, gender-, and ethnicity-matched healthy controls. While the REs distribution was similar between the ALS and control groups, a moderate association was observed between longer RE lengths and clinical features such as age at onset, gender, site of onset, and family history. In conclusion, this is the first study to screen ALS patients from southern Italy for REs in NIPA1, NOP56, and NOTCH2NLC genes, contributing to our understanding of ALS genetics. Our results highlighted that the extremely rare pathogenic REs in these genes do not allow an association with the disease.

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Section: Discussionmentioning

confidence: 87%

Investigating Repeat Expansions in NIPA1, NOP56, and NOTCH2NLC Genes: A Closer Look at Amyotrophic Lateral Sclerosis Patients from Southern Italy

Ruffo,

De Amicis,

La Bella

et al. 2024

Cells

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show abstract

“…More rapid disease progression was also noted in a Maltese ALS patient with a heterozygous NIPA1 expansion of more than 8 repeats [ 46 ]. A non-significant association between spinal onset, and earlier disease onset and NIPA1 alleles of more than 8 repeats was also observed in two unrelated studies [ 60 , 61 ].…”

Section: Introductionmentioning

confidence: 79%

Beyond C9orf72: repeat expansions and copy number variations as risk factors of amyotrophic lateral sclerosis across various populations

Nagy,

Pál,

Engelhardt

et al. 2024

BMC Med Genomics

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which is characterized by the loss of both upper and lower motor neurons in the central nervous system. In a significant fraction of ALS cases - irrespective of family history- a genetic background may be identified. The genetic background of ALS shows a high variability from one ethnicity to another. The most frequent genetic cause of ALS is the repeat expansion of the C9orf72 gene. With the emergence of next-generation sequencing techniques and copy number alteration calling tools the focus in ALS genetics has shifted from disease causing genes and mutations towards genetic susceptibility and risk factors.In this review we aimed to summarize the most widely recognized and studied ALS linked repeat expansions and copy number variations other than the hexanucleotide repeat expansion in the C9orf72 gene. We compare and contrast their involvement and phenotype modifying roles in ALS among different populations.

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“…In addition to NIPA1, repeat expansions in C9orf72 and ATXN2 have also been reported in ALS (Elden et al, 2010;DeJesus-Hernandez et al, 2011). However, NIPA1 repeat length was not confirmed to be a modifier of the C9orf72 ALS disease risk (Corrado et al, 2019).…”

Section: Discussionmentioning

confidence: 95%

Clinical and Genetic Features of Chinese Patients With NIPA1-Related Hereditary Spastic Paraplegia Type 6

Jun

et al. 2022

Front. Genet.

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Background: Mutations in the NIPA1 gene cause hereditary spastic paraplegia (HSP) type 6 (SPG6), which is a rare type of HSP with a frequency of less than 1% in Europe. To date, less than 30 SPG6 families and limited NIPA1 mutations have been reported in different ethnic regions. The clinical features are variable.Methods: We screened for NIPA1 mutations by whole exome sequencing or next generation sequencing in 35 unrelated Chinese families with HSP. The clinical manifestations were evaluated.Results: Two variants of NIPA1 were identified in three index patients (3/35, 8.6%), two of whom carried a previously reported common variant c.316G > A (p.G106R), and the third patient harbored a novel likely pathogenic variant c.126C > G (p.N42K). Both variants were de novo in the three index patients. The phenotype was pure HSP in two patients and complicated HSP with epilepsy in the third one.Conclusion:NIPA1-related HSP is more common in China than it in Europe. Both pure and complicated form of HSP can be found. The variant c.316G > A is a hotspot mutation, and the novel variant c.126C > G expands the mutational spectrum. The phenomenon of de novo mutations in NIPA1 emphasizes the need to consider autosomal dominant HSP-related genes in sporadic patients.

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Analysis of the GCG repeat length in NIPA1 gene in C9orf72-mediated ALS in a large Italian ALS cohort

Cited by 8 publications

References 7 publications

Investigating Repeat Expansions in NIPA1, NOP56, and NOTCH2NLC Genes: A Closer Look at Amyotrophic Lateral Sclerosis Patients from Southern Italy

Investigating Repeat Expansions in NIPA1, NOP56, and NOTCH2NLC Genes: A Closer Look at Amyotrophic Lateral Sclerosis Patients from Southern Italy

Beyond C9orf72: repeat expansions and copy number variations as risk factors of amyotrophic lateral sclerosis across various populations

Clinical and Genetic Features of Chinese Patients With NIPA1-Related Hereditary Spastic Paraplegia Type 6

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