Association of Copy Numbers of Survival Motor Neuron Gene 2 and Neuronal Apoptosis Inhibitory Protein Gene With the Natural History in a Chinese Spinal Muscular Atrophy Cohort

Qu, Yue; Ge, Xiushan; Bai, Jianling; Wang, Liwen; Cao, Yunxia; Lü, Yanyu; Jin, Yue; Wang, Hong; Song, Fang

doi:10.1177/0883073814553271

Cited by 32 publications

(37 citation statements)

References 28 publications

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“…Our previous study showed that cases with homozygous deletion variants phenotypically have type II or III SMA when they also have three copies of SMN2. 10 Thus, it is possible that the increased number of SMN2 gene copies alleviated the phenotype in this child.…”

Section: Influencing the Correct Splicing Of Smn1mentioning

confidence: 94%

Mutation Spectrum of the Survival of Motor Neuron 1 and Functional Analysis of Variants in Chinese Spinal Muscular Atrophy

Bai

Cao

et al. 2016

The Journal of Molecular Diagnostics

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Proximal spinal muscular atrophy (SMA) is a common fatal autosomal recessive disorder caused by deletion or mutation of the survival of motor neuron 1 (SMN1). Here, we studied SMA molecular pathology in 653 Chinese patients and found approximately 88.2% with homozygous SMN1 exon 7 deletion and 6.3% with heterozygous exon 7 loss using multiplex ligation-dependent probe amplification. SMN1 variants were detected in 34 patients with heterozygous SMN1 loss by clone sequencing. In 27 of them, 15 variants were identified: five were unreported novel variants [c.-7_9del(p.0), p.Tyr109Cys, p.Ile249Tyrfs*16, p.Tyr272Trpfs*35, and c.835-5T>G], five were previously found only in Chinese patients (p.Ser8Lysfs*23, p.Gln14*, p.Val19Glyfs*21, p.Leu228*, and p.Tyr277Cys), and five were reported in other populations [p.Ala2Gly, p.Gln15*, p.Glu134Lys, p.Ser230Leu, and c.863G>T (r.835_*3del, p.Gly279Glufs*5)]. Variants p.Ser8Lysfs*23 and p.Leu228* were the most common in Chinese SMA. Five variants (p.Ser8Lysfs*23, p.Gln14*, p.Gln15*, p.Val19Glyfs*21, and p.Leu228*) resulted in premature stop codons, likely causing SMN1 mRNA nonsense-mediated decay. The novel variant c.-7_9del (p.0) caused deletion of the translation start codon (AUG), resulting in full-length SMN protein loss. The novel variant c.835-5T>G, located in a splice site, resulted in 90% exon 7 skipping. Our study could facilitate early diagnosis for SMA patients in mutation detection and revealed the specific mutation spectrum of SMN1 in Chinese SMA and high genetic heterogeneity in subtle variants observed between patients from China and Caucasians.

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Section: Influencing the Correct Splicing Of Smn1mentioning

confidence: 94%

Mutation Spectrum of the Survival of Motor Neuron 1 and Functional Analysis of Variants in Chinese Spinal Muscular Atrophy

Bai

Cao

et al. 2016

The Journal of Molecular Diagnostics

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“…NAIP was given its name because it bore a baculoviral IAP repeat (BIR) domain, and was initially thought to regulate survival of neurons. While NAIP loss in neurons, or other cells, is not the main cause of SMA, it does appear to modify the severity of the disease depending on the gene copy numbers present [84]. The closest mouse homologue is Naip2.…”

Section: The Naip Gene Familymentioning

confidence: 97%

IAP gene deletion and conditional knockout models

Silke

Vaux

2015

Seminars in Cell & Developmental Biology

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“…In a study of Chinese patients, Fang et al21 compared copy numbers of SMN1 , SMN2 , and NAIP in SMA patients and healthy controls and produced evidence of differences in copy numbers and gene structure between the SMA patients and controls. Qu et al22 further investigated the association of copy numbers of SMN2 and NAIP with the disease course in SMA patients, and found that patients with fewer copies of SMN2 and NAIP were characterized by a higher risk of death and a lower survival rate.…”

Section: Discussionmentioning

confidence: 99%

Genotype-Phenotype Correlation ofSMN1andNAIPDeletions in Korean Patients with Spinal Muscular Atrophy

et al. 2017

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Background and PurposeSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness and atrophy. Most SMA patients have a homozygous deletion in survival of motor neuron 1 (SMN1) gene, and neuronal apoptosis inhibitory protein (NAIP) gene is considered a phenotype modifier. We investigated the genotype-phenotype correlation of SMN1 and NAIP deletions in Korean SMA patients.MethodsThirty-three patients (12 males and 21 females) treated at the Asan Medical Center between 1999 and 2013 were analyzed retrospectively. The polymerase chain reaction (PCR), restriction-fragment-length polymorphism analysis, and multiplex PCR were used to detect deletions in SMN1 (exons 7 and 8) and NAIP (exons 4 and 5). We reviewed clinical presentations and outcomes and categorized the patients into three clinical types. NAIP deletion-driven differences between the two genotypes were analyzed.ResultsDeletion analysis identified homozygous deletions of SMN1 exons 7 and 8 in 30 patients (90.9%). Among these, compared with patients without an NAIP deletion, those with an NAIP deletion showed a significantly lower age at symptom onset (1.9±1.7 months vs. 18.4±20.4 months, mean±SD; p=0.007), more frequent type 1 phenotype (6/6 vs. 8/24, p=0.005), and worse outcomes, with early death or a requirement for ventilator support (4/4 vs. 2/12, p=0.008).ConclusionsHomozygous deletion in SMN1 and a concurrent NAIP deletion were associated with an early onset, severe hypotonia, and worse outcome in SMA patients. Deletion analysis of NAIP and SMN1 can help to accurately predict prognostic outcomes in SMA.

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Association of Copy Numbers of Survival Motor Neuron Gene 2 and Neuronal Apoptosis Inhibitory Protein Gene With the Natural History in a Chinese Spinal Muscular Atrophy Cohort

Cited by 32 publications

References 28 publications

Mutation Spectrum of the Survival of Motor Neuron 1 and Functional Analysis of Variants in Chinese Spinal Muscular Atrophy

Mutation Spectrum of the Survival of Motor Neuron 1 and Functional Analysis of Variants in Chinese Spinal Muscular Atrophy

IAP gene deletion and conditional knockout models

Genotype-Phenotype Correlation ofSMN1andNAIPDeletions in Korean Patients with Spinal Muscular Atrophy

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