Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers in some spinal muscular atrophy (SMA) patients

Yamamoto, Tomoto; Sato, Hideyuki; Lai, Poh San; Nurputra, Dian Kesumapramudya; Harahap, Nur Imma Fatimah; Morikawa, Satoru; Nishimura, Noriyuki; Kurashige, Takashi; Ohshita, Tomohiko; Nakajima, Hideki; Yamada, Hiroyuki; Nishida, Yoshihiro; Toda, Soichiro; Takanashi, Jun‐ichi; Takeuchi, Atsuko; Tohyama, Yumi; Kubo, Yohei; Saito, Kayoko; Takeshima, Yasuhiro; Matsuo, Masafumi; Nishio, Hisahide

doi:10.1016/j.braindev.2013.11.009

Cited by 46 publications

(45 citation statements)

References 37 publications

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“…Indeed, SMN2 copy number variation is the best known modifier of SMA, potentially masking the phenotype of SMN1 point mutants [4]. However, SMN2 copy number is not always predictive of SMA disease severity [52]. Thus, developing an animal model that is an accurate predictor of SMN protein function is an important goal.…”

Section: Resultsmentioning

confidence: 99%

SMA-Causing Missense Mutations in Survival motor neuron (Smn) Display a Wide Range of Phenotypes When Modeled in Drosophila

et al. 2014

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Mutations in the human survival motor neuron 1 (SMN) gene are the primary cause of spinal muscular atrophy (SMA), a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of phenotypic severities, similar to the human disease. Furthermore, specific interactions with other proteins known to be important for SMN's role in RNP assembly are conserved. Intragenic complementation analyses revealed that the three most severe mutations, all of which map to the YG box self-oligomerization domain of SMN, display a stronger phenotype than the null allele and behave in a dominant fashion. In support of this finding, the severe YG box mutants are defective in self-interaction assays, yet maintain their ability to heterodimerize with wild-type SMN. When expressed at high levels, wild-type SMN is able to suppress the activity of the mutant protein. These results suggest that certain SMN mutants can sequester the wild-type protein into inactive complexes. Molecular modeling of the SMN YG box dimer provides a structural basis for this dominant phenotype. These data demonstrate that important structural and functional features of the SMN YG box are conserved between vertebrates and invertebrates, emphasizing the importance of self-interaction to the proper functioning of SMN.

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Section: Resultsmentioning

confidence: 99%

SMA-Causing Missense Mutations in Survival motor neuron (Smn) Display a Wide Range of Phenotypes When Modeled in Drosophila

et al. 2014

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“…8 This frame-shifting mutation, which has already been registered in LOVD database (http://www.dmd.nl/nmdb2/home.php?select_db¼SMN1), causes disruption of the C-terminal domain of FL-SMN1 protein (p.Thr274TyrfsX32). The "QNQKE" motif was absent in patient 1 because of the frame-shifting mutation.…”

Section: Molecular Genetic Analysismentioning

confidence: 99%

Two Japanese Patients With SMA Type 1 Suggest that Axonal-SMN May Not Modify the Disease Severity

Yamada

Nishida

Maihara

et al. 2015

Pediatric Neurology

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“…The spectrum ranges from fetuses that die in utero or soon after birth (type 0), infants born noticeably afflicted who die within 2 years of birth (type I), patients able to sit upright but not walk and who survive into their teens and adulthood (type II), patients able to walk independently with a normal or near normal lifespan (type III) and patients with adult-onset progressive muscle weakness (type IV). Barring a few exceptions [1,10–11], the copy number of SMN2 appears to correlate at least partially with SMA disease severity [12–14]. Increased SMN2 copy number may result from increased conversion of SMN1 to SMN2 or duplication of SMN2 [15,16].…”

Section: Spinal Muscular Atrophy: Genetics and Phenotypementioning

confidence: 99%

“…The interaction of SMN with Gemin2 has been suggested to be important for several SMN functions including small nuclear ribonucleoprotein (snRNP) biogenesis [19], signal recognition particle biogenesis [20], DNA recombination [21], motor neuron trafficking of mRNAs [22] and translation regulation [23]. Point mutations across the entire primary structure of the protein have been linked to SMA pathogenesis (Figure 1C; Supplementary Table 1) [1–3,11,24–55]. None of the deletions or missense mutations of SMN produce toxic effects and/or generate protein aggregates.…”

Section: Structure–function Relationship In Smnmentioning

confidence: 99%

Advances in Therapeutic Development for Spinal Muscular Atrophy

Howell

Singh

2014

Future Med. Chem.

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Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The disease originates from low levels of SMN protein due to deletion and/or mutations of SMN1 coupled with the inability of SMN2 to compensate for the loss of SMN1. While SMN1 and SMN2 are nearly identical, SMN2 predominantly generates a truncated protein (SMNΔ7) due to skipping of exon 7, the last coding exon. Several avenues for SMA therapy are being explored, including means to enhance SMN2 transcription, correct SMN2 exon 7 splicing, stabilize SMN/SMNΔ7 protein, manipulate SMN-regulated pathways and SMN1 gene delivery by viral vectors. This review focuses on the aspects of target discovery, validations and outcome measures for a promising therapy of SMA.

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Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers in some spinal muscular atrophy (SMA) patients

Cited by 46 publications

References 37 publications

SMA-Causing Missense Mutations in Survival motor neuron (Smn) Display a Wide Range of Phenotypes When Modeled in Drosophila

SMA-Causing Missense Mutations in Survival motor neuron (Smn) Display a Wide Range of Phenotypes When Modeled in Drosophila

Two Japanese Patients With SMA Type 1 Suggest that Axonal-SMN May Not Modify the Disease Severity

Advances in Therapeutic Development for Spinal Muscular Atrophy

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