Human Disease Model Report: spinal muscular atrophy, SMN2-related therapy

General Information

Name

spinal muscular atrophy, SMN2-related therapy

FlyBase ID

FBhh0001004

Disease Ontology Term

spinal muscular atrophy

Parent Disease

OMIM

Overview

The SMN complex plays a role in the assembly of small nuclear ribonucleoproteins (snRNPs) into the spliceosome. In human, the two SMN complex genes SMN1 and SMN2 are nearly identical. A single nucleotide sequence difference results in different splicing patterns and production of a truncated protein from SMN2 90% of the time. Loss-of-function variants in SMN1 result in spinal muscular atrophy (see FBhh0000352); it has been shown that increased production of the full-length SMN2 protein can functionally compensate for SMN1.

A transgene carrying human Hsap\SMN2 exons 6 to 8 has been introduced into flies to test therapeutic approaches targeting SMN2 splicing (exon 7 inclusion allows production of the full-length protein). The efficacy of the compound designated PK4C9 was validated in this fly system.

[updated Apr. 2019 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: spinal muscular atrophy, SMN2-related therapy

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

The SMN1 and SMN2 genes lie within the telomeric and centromeric halves, respectively, of a large, inverted duplication on chromosome 5q13. These genes share more than 99% nucleotide identity, and both are capable of encoding a 294-amino acid RNA-binding protein, SMN, that is required for efficient assembly of small nuclear ribonucleoprotein (snRNP) complexes. Homozygous loss of the SMN1 gene causes spinal muscular atrophy (SMA; 253300). Absence of SMN1 is partially compensated for by SMN2, which produces enough SMN protein to allow for relatively normal development in cell types other than motor neurons (Lefebvre et al., 1995, pubmed:7813012; Kashima et al., 2007, pubmed:17884807). [from MIM:601627; 2019.04.16]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

The SMN complex plays a catalyst role in the assembly of small nuclear ribonucleoproteins (snRNPs) into the spliceosome. [Gene Cards, SMN1; 2016.04.16]

(FlyBase Curators, 2013-)

SMN2 cannot fully compensate for loss of SMN1 because, although SMN2 is transcribed at a level comparable to that of SMN1, a large majority of SMN2 transcripts lack exon 7, resulting in production of a truncated, less stable SMN protein (Lefebvre et al., 1995, pubmed:7813012; Kashima et al., 2007, pubmed:17884807). [from MIM:601627; 2019.04.16]

(OMIM, 2013-)

External links