Chapter 8. Identification of a Novel Class of Small Molecules for Spinal Muscular Atrophy Through High-throughput Phenotypic Screening

2020 ◽  
pp. 140-159
Author(s):  
Susanne E. Swalley ◽  
Atwood K. Cheung
Keyword(s):  
Spinal Muscular Atrophy ◽  
Small Molecules ◽  
High Throughput ◽  
Muscular Atrophy ◽  
Phenotypic Screening

scholarly journals Automated screening ofC. elegansneurodegeneration mutants enabled by microfluidics and image analysis algorithms

2018 ◽  
Vol 10 (9) ◽  
pp. 539-548 ◽  
Author(s):  
Ivan de Carlos Cáceres ◽  
Daniel A. Porto ◽  
Ivan Gallotta ◽  
Pamela Santonicola ◽  
Josue Rodríguez-Cordero ◽  
...  
Keyword(s):  
Image Analysis ◽  
Spinal Muscular Atrophy ◽  
High Throughput ◽  
Muscular Atrophy ◽  
High Throughput Screen ◽  
C Elegans ◽  
Genetic Mechanisms ◽  
Automated Screening

A fully automated high-throughput screen usingC. elegansto investigate genetic mechanisms affecting spinal muscular atrophy (SMA).

scholarly journals High-throughput screening reveals novel mutations in spinal muscular atrophy patients

2019 ◽  
Author(s):  
Jianbo Shu ◽  
Jingrui Wang ◽  
Yulian Fang ◽  
Zanmei Xu ◽  
Xiaowei Wang ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
High Throughput ◽  
High Throughput Screening ◽  
High Throughput Sequencing ◽  
Muscular Atrophy ◽  
Point Mutations ◽  
Control Group ◽  
Compound Heterozygous ◽  
Single Nucleotide Variants ◽  
Illumina Hiseq

Abstract Background Some spinal muscular atrophy (SMA) cases are caused by either compound heterozygosity with a point mutation in one allele and a deletion in the other or compound heterozygous point mutations in SMN1 or other genes. Methods To explore more genes and mutations in the onset of SMA, 83 whole blood samples were collected from 28 core families of clinically suspected SMA, and multiplex ligation probe amplification (MLPA) was firstly performed with a SALSA MLPA Kit P021 for preliminary diagnosis. Afterwards, the complete gene sequence of SMN1 gene was detected with the high-throughput sequencing platform of Illumina HiSeq-2500 to find more mutations in the 28 core families. Furthermore, 20 SMA patients were selected from the 28 prodands, and 5 non SMA children as controls. The Life Technologies SOLiD™ technology with mate-pair chemistry was utilized to conduct the whole exome high-throughput sequencing. Results MLPA results showed that 22 probands were SMA patients, 3 probands carriers, and 3 probands normal individuals. Moreover, 2 parents from 2 SMA families were with 3 SMN1 exon7 copies. 6 SMN1 single nucleotide variants (SNVs) were identified in the 83 samples, and c.[84C>T], c.[271C>T], c.[-39A>G] and g.[70240639G>C] were novel. Compared with control group, 9102 mutation were selected out in SMA patients. SPTA1 mutation c.[-41_-40insCTCT], FUT5 SNV c.[1001A>G], and MCCC2 SNV c.[-117A>G] were the 3 most frequent mutations in SMA group (95%, 85% and 75%, respectively). Conclusions We identified some mutations in both SMN1 and other genes, and c.[271C>T], c.[-41_-40insCTCT], c.[1001A>G] and c.[-117A>G] might be associated with the onset of SMA.

scholarly journals Small Molecules in Development for the Treatment of Spinal Muscular Atrophy

2016 ◽  
Vol 59 (22) ◽  
pp. 10067-10083 ◽  
Author(s):  
Alyssa N. Calder ◽  
Elliot J. Androphy ◽  
Kevin J. Hodgetts
Keyword(s):  
Spinal Muscular Atrophy ◽  
Small Molecules ◽  
Muscular Atrophy

scholarly journals Diverse small-molecule modulators of SMN expression found by high-throughput compound screening: early leads towards a therapeutic for spinal muscular atrophy

2005 ◽  
Vol 14 (14) ◽  
pp. 2003-2018 ◽  
Author(s):  
Jill Jarecki ◽  
Xiaocun Chen ◽  
Alexandra Bernardino ◽  
Daniel D. Coovert ◽  
Michael Whitney ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Small Molecule ◽  
High Throughput ◽  
Muscular Atrophy ◽  
Compound Screening ◽  
Small Molecule Modulators

scholarly journals High-throughput screening reveals novel mutations in spinal muscular atrophy patients

2020 ◽  
Vol 46 (1) ◽  
Author(s):  
Ruiping Zhang ◽  
Chunyu Gu ◽  
Linjie Pu ◽  
Yingtao Meng ◽  
Jianbo Shu ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
High Throughput ◽  
High Throughput Screening ◽  
High Throughput Sequencing ◽  
Muscular Atrophy ◽  
Hereditary Disease ◽  
Control Group ◽  
Single Nucleotide Variants ◽  
Frequent Mutations ◽  
Multiplex Ligation Probe Amplification

Abstract Background Spinal muscular atrophy (SMA) is an autosomal recessive hereditary disease associated with severe muscle atrophy and weakness in the limbs and trunk. The discovery of mutated genes is helpful in diagnosis and treatment for SMA. Methods Eighty-three whole blood samples were collected from 28 core families of clinically suspected SMA, and multiplex ligation probe amplification (MLPA) was performed. Afterwards, the complete gene sequence of SMN1 gene was detected. Furthermore, 20 SMA patients were selected from the 28 probands, and 5 non SMA children as controls. The Life Technologies SOLiD™ technology with mate-pair chemistry was utilized to conduct the whole exome high-throughput sequencing. Results Twenty-two probands were SMA patients, 3 probands carriers, and 3 probands normal individuals. Moreover, 2 parents from 2 SMA families were with 3 SMN1 exon7 copies. Six SMN1 single nucleotide variants (SNVs) were identified in the 83 samples, and c.[84C > T], c.[271C > T], c.[−39A > G] and g.[70240639G > C] were novel. Compared with control group, 9102 mutation were selected out in SMA patients. SPTA1 mutation c.[−41_-40insCTCT], FUT5 SNV c.[1001A > G], and MCCC2 SNV c.[−117A > G] were the 3 most frequent mutations in SMA group (95, 85 and 75%, respectively). Conclusions We identified some mutations in both SMN1 and other genes, and c.[271C > T], c.[−41_-40insCTCT], c.[1001A > G] and c.[−117A > G] might be associated with the onset of SMA.

scholarly journals High-throughput screening reveals novel mutations in spinal muscular atrophy patients

2020 ◽  
Author(s):  
Ruiping Zhang ◽  
Chunyu Gu ◽  
Linjie Pu ◽  
Yingtao Meng ◽  
Jianbo Shu ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
High Throughput ◽  
High Throughput Screening ◽  
High Throughput Sequencing ◽  
Muscular Atrophy ◽  
Hereditary Disease ◽  
Control Group ◽  
Single Nucleotide Variants ◽  
Frequent Mutations ◽  
Multiplex Ligation Probe Amplification

Abstract Background Spinal muscular atrophy (SMA) is an autosomal recessive hereditary disease associated with severe muscle atrophy and weakness in the limbs and trunk. The discovery of genes mutated by SMA is helpful in diagnosis and treatment. Methods 83 whole blood samples were collected from 28 core families of clinically suspected SMA, and multiplex ligation probe amplification (MLPA) was firstly performed. Afterwards, the complete gene sequence of SMN1 gene was detected. Furthermore, 20 SMA patients were selected from the 28 probands, and 5 non SMA children as controls. The Life Technologies SOLiD™ technology with mate-pair chemistry was utilized to conduct the whole exome high-throughput sequencing. Results 22 probands were SMA patients, 3 probands carriers, and 3 probands normal individuals. Moreover, 2 parents from 2 SMA families were with 3 SMN1 exon7 copies. 6 SMN1 single nucleotide variants (SNVs) were identified in the 83 samples, and c.[84C>T], c.[271C>T], c.[-39A>G] and g.[70240639G>C] were novel. Compared with control group, 9102 mutation were selected out in SMA patients. SPTA1 mutation c.[-41_-40insCTCT], FUT5 SNV c.[1001A>G], and MCCC2 SNV c.[-117A>G] were the 3 most frequent mutations in SMA group (95%, 85% and 75%, respectively). Conclusions We identified some mutations in both SMN1 and other genes, and c.[271C>T], c.[-41_-40insCTCT], c.[1001A>G] and c.[-117A>G] might be associated with the onset of SMA.

scholarly journals High-throughput screening reveals novel mutations in spinal muscular atrophy patients

2020 ◽  
Author(s):  
Ruiping Zhang ◽  
Chunyu Gu ◽  
Linjie Pu ◽  
Yingtao Meng ◽  
Jianbo Shu ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
High Throughput ◽  
High Throughput Screening ◽  
High Throughput Sequencing ◽  
Muscular Atrophy ◽  
Hereditary Disease ◽  
Control Group ◽  
Single Nucleotide Variants ◽  
Frequent Mutations ◽  
Multiplex Ligation Probe Amplification

Abstract Background: Spinal muscular atrophy (SMA) is an autosomal recessive hereditary disease associated with severe muscle atrophy and weakness in the limbs and trunk. The discovery of mutated genes is helpful in diagnosis and treatment for SMA. Methods: 83 whole blood samples were collected from 28 core families of clinically suspected SMA, and multiplex ligation probe amplification (MLPA) was performed. Afterwards, the complete gene sequence of SMN1 gene was detected. Furthermore, 20 SMA patients were selected from the 28 probands, and 5 non SMA children as controls. The Life Technologies SOLiD™ technology with mate-pair chemistry was utilized to conduct the whole exome high-throughput sequencing. Results: 22 probands were SMA patients, 3 probands carriers, and 3 probands normal individuals. Moreover, 2 parents from 2 SMA families were with 3 SMN1 exon7 copies. 6 SMN1 single nucleotide variants (SNVs) were identified in the 83 samples, and c.[84C>T], c.[271C>T], c.[-39A>G] and g.[70240639G>C] were novel. Compared with control group, 9102 mutation were selected out in SMA patients. SPTA1 mutation c.[-41_-40insCTCT], FUT5 SNV c.[1001A>G], and MCCC2 SNV c.[-117A>G] were the 3 most frequent mutations in SMA group (95%, 85% and 75%, respectively). Conclusions: We identified some mutations in both SMN1 and other genes, and c.[271C>T], c.[-41_-40insCTCT], c.[1001A>G] and c.[-117A>G] might be associated with the onset of SMA.

Sign in / Sign up

Export Citation Format

Share Document