Passage
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease affecting 1 in 10,000 live births. The pathological hallmark of SMA is the loss of α-motor neurons in the spinal cord, which causes progressive paralysis and, ultimately, premature death in infants. SMA is caused by insufficient levels of survival motor neuron (SMN) , a regulatory protein required for the maintenance of the spinal cord nerve cells that control voluntary muscle movement.The SMN protein is generated from the SMN1 and SMN2 genes, which differ in sequence by only a single nucleotide in exon 7. In healthy individuals, the gene product of SMN1 is the full-length (FL) SMN protein, and the gene products of SMN2 are both the FL-SMN protein as well as a truncated unstable protein (SMNΔ7) that is rapidly degraded. Approximately 90% of the SMN2 gene product is SMNΔ7, and only 10% is FL-SMN (Figure 1) . In most patients with SMA, SMN1 is mutated such that its protein product is nonfunctional or deleted. The disease phenotype arises because the SMN2 gene cannot fully compensate for the deficiency in FL-SMN protein synthesis.
Figure 1 Structure of SMN1 and SMN2 transcriptsAntisense oligonucleotides (ASOs) that bind pre-mRNA were injected into SMA mice (SMN1^−/−, SMN2^+/+) exhibiting progressive tail necrosis, a characteristic measure of SMA severity. ASO therapy effectiveness was assessed by measuring the tail length of wild-type (WT) mice and SMA mice exposed to increasing concentrations of ASOs (Figure 2) .
Figure 2 Tail length progression of WT mice compared to SMA mice treated with either saline or ASOs
Adapted from Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA. 1999;96(11) :6307-11.
-What steps are required to produce a mature FL-SMN transcript?Excision of noncoding sequences between the 3′ and 5′ untranslated regions in pre-mRNAAddition of multiple adenine nucleotides to the 3′ end of SMN1 pre-mRNARemoval of the 7-methylguanosine cap from mature mRNADNA polymerase binding to the SMN1 gene

Question

Passage
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease affecting 1 in 10,000 live births. The pathological hallmark of SMA is the loss of α-motor neurons in the spinal cord, which causes progressive paralysis and, ultimately, premature death in infants. SMA is caused by insufficient levels of survival motor neuron (SMN) , a regulatory protein required for the maintenance of the spinal cord nerve cells that control voluntary muscle movement.The SMN protein is generated from the SMN1 and SMN2 genes, which differ in sequence by only a single nucleotide in exon 7. In healthy individuals, the gene product of SMN1 is the full-length (FL) SMN protein, and the gene products of SMN2 are both the FL-SMN protein as well as a truncated unstable protein (SMNΔ7) that is rapidly degraded. Approximately 90% of the SMN2 gene product is SMNΔ7, and only 10% is FL-SMN (Figure 1) . In most patients with SMA, SMN1 is mutated such that its protein product is nonfunctional or deleted. The disease phenotype arises because the SMN2 gene cannot fully compensate for the deficiency in FL-SMN protein synthesis.

Figure 1 Structure of SMN1 and SMN2 transcriptsAntisense oligonucleotides (ASOs) that bind pre-mRNA were injected into SMA mice (SMN1^−/−, SMN2^+/+) exhibiting progressive tail necrosis, a characteristic measure of SMA severity. ASO therapy effectiveness was assessed by measuring the tail length of wild-type (WT) mice and SMA mice exposed to increasing concentrations of ASOs (Figure 2) .

Figure 2 Tail length progression of WT mice compared to SMA mice treated with either saline or ASOs
Adapted from Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA. 1999;96(11) :6307-11.
-What steps are required to produce a mature FL-SMN transcript?Excision of noncoding sequences between the 3′ and 5′ untranslated regions in pre-mRNAAddition of multiple adenine nucleotides to the 3′ end of SMN1 pre-mRNARemoval of the 7-methylguanosine cap from mature mRNADNA polymerase binding to the SMN1 gene

Quizplus · Accepted Answer

11ecba2d_0f97_e46a_a3bf_f518463c1afb_MD0008_00 Transcription is the process in which the nucleotide sequence of a DNA region is used as a template to synthesize a new RNA strand. Messenger RNA (mRNA) is the type of RNA molecule produced for the transcription of protein-expressing genes. Transcription begins with the binding of transcription factors and RNA polymerase II to a specific AT-rich sequence (TATA box) in the promoter region of double-stranded DNA. RNA polymerase II processes the noncoding DNA strand in a 3′ to 5′ direction until a termination sequence is recognized. As the enzyme travels down the DNA strand, it unravels the DNA double helix and relies on the complementary pairing of bases to catalyze the synthesis of a pre-mRNA strand, which grows in the 5′ to 3′ direction. The pre-mRNA molecule generally undergoes the following modifications to be converted into mature mRNA: A 7-methylguanosine (5′ cap) is added to the 5′ end of pre-mRNA as the nascent transcript is being generated. This 5′ cap is later recognized by the ribosome during translation and prevents the degradation of mRNA in the cytoplasm (Number III). A chain of adenine nucleotides known as the poly-A tail is added to the 3′ end of the mRNA. This poly-A tail functions to prevent the mRNA from being degraded and also facilitates the export of the mature mRNA from the nucleus to the cytoplasm (Number II). In pre-mRNA, there are non-coding (introns) and coding regions (exons) located between two untranslated regions (sequences that regulate translation but do not code for amino acids). The noncoding regions (introns) are excised from the pre-mRNA molecule, and the remaining untranslated and coding regions are joined via splicing (Number I). (Number IV) DNA polymerase catalyzes the synthesis of DNA molecules (replication) and is not involved in transcription. Educational objective: Transcription is the process of synthesizing RNA from template DNA and begins with RNA polymerase II binding to the gene promoter region. RNA polymerase II reads the DNA strand in a 3′ to 5′ direction to generate a 5′ to 3′ pre-mRNA molecule. The pre-mRNA transcript undergoes 5′ capping, the addition of a 3′ poly-A tail, and excision of noncoding regions (introns) to be converted into mature mRNA.