Phenotypes of SMA patients retaining SMN1 with intragenic mutation

Phenotypes of SMA patients retaining SMN1 with intragenic mutation

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous deletion or intragenic mutation of the SMN1 gene. It is well-known that high copy number of its homologous gene, SMN2, modifies the phenotype of SMN1-deleted patients. However, in the patients with in...

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Bibliographic Details
Published in:Brain & development (Tokyo. 1979) Vol. 43; no. 7; pp. 745 - 758
Main Authors: Wijaya, Yogik Onky Silvana, Ar Rohmah, Mawaddah, Niba, Emma Tabe Eko, Morisada, Naoya, Noguchi, Yoriko, Hidaka, Yasufumi, Ozasa, Shiro, Inoue, Takeshi, Shimazu, Tomoyuki, Takahashi, Yuya, Tozawa, Takenori, Chiyonobu, Tomohiro, Inoue, Takushi, Shiroshita, Tomoyoshi, Yokoyama, Atsushi, Okamoto, Kentaro, Awano, Hiroyuki, Takeshima, Yasuhiro, Saito, Toshio, Saito, Kayoko, Nishio, Hisahide, Shinohara, Masakazu
Format: Journal Article
Language:English
Published: Netherlands Elsevier B.V 01-08-2021
Subjects:
Adolescent
Child
Female
Humans
Infant
Infant, Newborn
Intragenic mutation
Long-range PCR
Male
Muscular Atrophy, Spinal - genetics
Muscular Atrophy, Spinal - physiopathology
Mutation
Patient Acuity
Phenotype
RT-PCR
SMN1
SMN2
Spinal muscular atrophy
Survival of Motor Neuron 1 Protein - genetics
Survival of Motor Neuron 2 Protein - genetics
SMN2
SMN1
RT-PCR
Spinal muscular atrophy
Intragenic mutation
Long-range PCR
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Summary:Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous deletion or intragenic mutation of the SMN1 gene. It is well-known that high copy number of its homologous gene, SMN2, modifies the phenotype of SMN1-deleted patients. However, in the patients with intragenic SMN1 mutation, the relationship between phenotype and SMN2 copy number remains unclear. We have analyzed a total of 515 Japanese patients with SMA-like symptoms (delayed developmental milestones, respiratory failures, muscle weakness etc.) from 1996 to 2019. SMN1 and SMN2 copy numbers were determined by quantitative polymerase chain reaction (PCR) method and/or multiplex ligation-dependent probe amplification (MLPA) method. Intragenic SMN1 mutations were identified through DNA and RNA analysis of the fresh blood samples. A total of 241 patients were diagnosed as having SMA. The majority of SMA patients showed complete loss of SMN1 (n = 228, 95%), but some patients retained SMN1 and carried an intragenic mutation in the retaining SMN1 (n = 13, 5%). Ten different mutations were identified in these 13 patients, consisting of missense, nonsense, frameshift and splicing defect-causing mutations. The ten mutations were c.275G > C (p.Trp92Ser), c.819_820insT (p.Thr274Tyrfs*32), c.830A > G (p.Tyr277Cys), c.5C > T (p.Ala2Val), c.826 T > C (p.Tyr276His), c.79C > T (p.Gln27*), c.188C > A (p.Ser63*), c.422 T > C (p.Leu141Pro), c.835-2A > G (exon 7 skipping) and c.835-3C > A (exon 7 skipping). It should be noted here that some patients with milder phenotype carried only a single SMN2 copy (n = 3), while other patients with severe phenotype carried 3 SMN2 copies (n = 4). Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers.
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ISSN:0387-7604
1872-7131
DOI:10.1016/j.braindev.2021.03.006