BibTex RIS Kaynak Göster

Spinal Muscular Atrophy and Its Molecular Genetics

Yıl 2012, Cilt: 21 Sayı: 1, 1 - 26, 01.03.2012

Öz

Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases, affecting aproximately 1 in 6,000 - 10,000 live births, and with a carrier frequency of aproximately 1 in 40- 60. The childhood SMAs can be classified clinically into three groups. Type I (Werdnig-Hoffmann) is the most severe form, with onset at ‹ 6 months of age and with death typically at ‹2 years of age. Type II SMA patients display an intermediate severity, with onset at ‹18 months of age and with an inability to walk. Type III (Kugelberg –Walender) individuals are able to walk independently and have a relatively mild phenotype, with onset at ›18 months of age. The gene involved in type I–III SMA has been mapped to 5q12-q13 by linkage analysis, and refined to a region of about 500 kb. The region contains a large inverted duplication consisting of at least four genes, which are present in a telomeric (t) and a centromeric (c) copy: survival motor neuron gene (SMN1 or SMNt and SMN2 or SMNc); neuronal apoptosis inhibitory protein gene (NAIP); basal transcription factor subunit p44 (BTFp44t and BTFp44c); and a novel protein with unknown function H4F5. Although homozygous deletions encompassing all these genes are found in SMA patients, it is now well established that mutations or deletions of SMN1 (MIM#600354) cause the disease. SMN2 (MIM# 601627) gene, however, does not prevent the disease but attenuates disease severity. Therefore, upregulating functional SMN protein level via inducing gene expression and/or restoring splicing is an important therapeutic approach such as use of histone deacetylase (HDAC) inhibitors.

Kaynakça

  • Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999
  • NAIP (Nöral Apoptozis İnhibitör Protein) Genomik uzunluğu 60 kb olan ve 16 ekzonu bulunan NAIP geni; 1232 amino asit uzunluğundaki 140 kD’luk bir proteini kodlar9. NAIP geni 1995 yılında SMA hastalarında delesyona uğrayan ikinci aday gen olarak tespit edilmiştir44. NAIP gen ekspresyonu doku özgüllüğü göstermez. Bu genin bir tam ve birden fazla kesikli kopyası vardır45. Hastalarda sadece tam kopyanın ve 6. ekzonlarında delesyon bulunması28,46nedeniyle delesyon analizi için tam kopyadaki ekzon 5 ve 6’nın multipleks PCR ile amplikasyonu yapılır ve delesyon varlığı araştırılır12.
  • SMA tip I grubunda yapılan 151. kodon ve 3’ucu 1939. nükleotid değişimi analizleri telomerik gende %53.5 oranında homozigot delesyon olduğunu göstermiştir12. Ancak, p44 geninde delesyon bulunduran hastaların tamamında SMN, bir kısmında da SMN ve NAIP genlerinde delesyon olması p44 genindeki mutasyonların hastalığın esas nedeni olmadığını düşündürmüştür. Bugüne kadar sadece p44 gen delesyonu bulunan bir SMA vakasının gösterilememiş olması genin tanı amaçlı olarak kullanılmasını ve önemini azaltmıştır12,27.
  • H4F5 ( SMA Modifiye Edici Gen 1) Scharf ve ark. tarafından 1998’de çok kopyalı mikrosatellit markır (C212) kullanılarak yapılan çalışmada, Tip I hastalarının %90’nında H4F5 gen bölgesinin delesyona uğradığı saptanmıştır. H4F5 geni tek başına SMA hastalığına yol açmazken hastalığın şiddeti üzerine etkili olmaktadır8,26,27.
  • McAndrew PE, Parsons DW, Simard LR, et al.Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. Am J Hum Genet 1997; 60:1411-22.
  • Parsons DW, McAndrew PE, Monani UR, et al. An 11 base pair duplication in exon 6 of the SMN gene produces a type I spinal muscular atrophy (SMA) phenotype: further evidence for SMN as the primary SMA-determining gene. Hum Mol Genet 1996 ; 5:1727-32. http://www.ncbi.nlm.nih.gov/books/NBK1352/ (Erişim tarih:04.2012)
  • Munsat T L. The Spinal Muscular Atrophies. Curr Neurology, 1994;4(3):55-71.
  • Bradley WG, Daroff RB, Fenichel GM, et al. Neurology in Clinical Practice Volume II.3th. Ed., Butterworth Heinemann., 2000; 1997-2004.
  • Brand T, Caplan LR, Dichgans J, et al. Neurological Disorders Course and Treatment. Academic Press USA. 1996; 814-815.
  • Bradley WG, Daroff RB, Fenichel GM, et al. Neurology in Clinical Practice Volume II.3th. Ed., Butterworth Heinemann., 2000; 1997-2004.
  • Rietschel M, Rudnick-Schonborn S, Zerres K. Clinical variability of autosomal dominant spinal muscular atrophy. J Neurol Sci 1992; 107:65-73.
  • Pehlivan s, Topaloğlu H, Erdem H. Centromeric survival motor neuron gene deletion in congenital muscular dystrophy. Balkan Journal of Medical Genetics (BJMG), 1999; (1):4142.
  • Migata M, Uchikoba Y, Orimo H, et al. Genetic diagnosis of Werdnig-Hoffman disease: A problem for application to prenatal diagnosis. J Nippon Med Sch 2003; 70 (1) :45-8. http://tr.wikipedia.org/wiki/Kromozom_5 ( Erişim tarih: 01. 2010) http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603011 (Erişim tarih: 09.2011)
  • Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000; 15:228-37.
  • Wirth B, Tessarolo D, Hahnen E, et al. Different entities of proximal spinal muscular atrophy within one family. Hum Genet 1997; 100:676–80.
  • Wirth B, Herz M, Wetter A, et al. Quantitative Analysis of survival motor neuron copies: ıdentification of subtle smn1 mutations in patients with spinal muscular atrophy, genotype- phenotype correlation, and ımplications for genetic counseling. Am J Hum Genet 1999; 64: –56. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603011 (Erişim tarih: 09.2011)
  • Zhang HL, Pan F, Hong D, et al. Active transport of the survival motor neuron protein and the role of exon-7 in cytoplasmic localization. J Neurosci, 2003; 23(16): 6627– 37.
  • Strasswimmer J, Lorson CL, Breiding DE ,Chen JJ, Le T, Burghes A, Androphy E. Identification of survival motor neuron as a transcriptional activator-binding protein .Human Mol Genet 1999; 8(7):1219-26.
  • Frugier T, Nicole S, Cifuentes-Diaz C et al. The molecular bases of spinal muscular atropy. Curr Opin Genet Dev 2002; 12:294-98. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600354 ( Erişim tarih: 06.2011)
  • Melki J, Lefebvre S, Burglen L, et al. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science 1994; 264:1474-77.
  • Jablonka S, Rossoll W, Schrank B, et al. The role of SMN in spinal muscular atrophy. J Neurol 2000; 247: 37–42.
  • Semprini S, Tacconellı A, Capon F, et al. A single strand conformation polymorphism-based carrier test for spinal muscular atrophy. Genetıc Testıng, 2001; 5: 33-7.
  • Le TT, Coovert DD, Monani UR, et al. The survival motor neuron (SMN) protein: effect of exon loss and mutation on protein localization. Neurogenetics 2000; 3:7–16.
  • Labrum R, Rodda J, Krause A. The molecular basis of Spinal Muscular Atrophy (SMA) in South African black patients. Neuromuscular Disorders 2007; 17: 684–92.
  • Amara A, Adala L, Charfeddine I B, et al. Correlation of SMN2, NAIP, p44, H4F5 and Occludin genes copy number with spinal muscular atrophy phenotype in Tunisian patients. European journal of Paediatric Neurology, 2012; 16:167 -74.
  • Zat’kova A, Hahnen E, Wirth B, et al. Analysis of the SMN and NAIP genes in Slovak spinal muscular atropy patients. Human Heredity 2000; 50:171-74.
  • Kocatürk-Sel S, Kasap H,Koç F. Spinal Müsküler atrofi hastalarında smn geni ekzon 7 ve ’in moleküler analizi / molecular analysis of exon 7 and 8 of smn gene in spinal muscular atrophy patients. Türk Nöroloji Dergisi 2006;12(5):353-61.
  • Kim CA, Passos-Bueno MR, Marie SK, et al. Clinical and molecular analysis of spinal muscular atrophy ın brazilian patients. Genet Mol Biology 1999; 22(4):487-92.
  • Roy N, Mahadevan MS, McLean M, et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 1995; 80:167-78.
  • Velasco E, Valero C, Valero A, et al.. Molecular analysis of the SMN and NAIP genes in Spanish spinal muscular atrophy (SMA) families and correlation between number of copies of cBCD541 and SMA phenotype. Hum Mol Genet 1996; 5:257-63.
  • Akutsu T, Nıshıo H, Sumıno K, et al. Molecular genetics of spinal muscular atrophy: contribution of the NAIP gene to clinical severity. Kobe J Med Sci, 2002; 48: 25-31.
  • Parsons DW, McAndrew PE, Iannaccone ST, et al. Intragenic telSMN Mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number. Am J Hum Genet 1998; 63:1712–23.
  • Desprez DG, Brun T, Rochette C, et al. The SMN genes are subject to transcriptional regulation during cellular differentiation. Gene, 2001; 279: 109- 117.
  • Fallini C, Bassell G J, W Rossolla. Spinal muscular atrophy: The role of SMN in axonal mRNA regulation.Brain Res. 2012 (Article in press)
  • Savaş S, Gokgoz N, Kayserili H, Ozkinay F, Yuksel-Apak M, Kirdar B. Screening of deletions in SMN, NAIP and BTF2p44 genes in Turkish spinal muscular atrophy patiens. Human Heredity , 2000; 50: 162-5.
  • Şimşek M, Bulushı TA, Shanmugakonar M, Barwanı HSA, Bayoumı R. Allele-Specific Amplification of Exon 7 in the Survival Motor Neuron (SMN) Genes for Molecular Diagnosis of Spinal Muscular Atrophy. Genet Testıng, 2003; 7: 325-7.
  • Chang J-G, Jong Y-J, Lin S-P, et al. Molecular analysis of Survival motor neuron (SMN) and neuronal apoptosisi inhibitory protein (NAIP) genes ao spinal muscular atrophy patients and their parents. Hum Genet, 1997;100: 577-81. http://internalmed.wustl.edu/divisions/enzymes/comRM.htm (Erişim tarih: 06.2005)
  • Mailman MD, Heinz JW, Papp AC, et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med, 2002; 4:20-26.
  • De-Maw Chuang, Yan Leng, Zoya Marinova, et al. Multiple roles of HDAC inhibition in neurodegenerative conditions Trends Neurosci. 2009; 32(11): 591–601.
  • Tatar G B, Dayangaç-Erden D, Erdem- Yurter H Spinal musküler atrofi tedavisinde histon deasetilaz inhibitörlerinin rolü. Hacettepe Tıp Dergisi 2010; 41:90-6.

Spinal Müsküler Atrofi ve Moleküler Genetiği

Yıl 2012, Cilt: 21 Sayı: 1, 1 - 26, 01.03.2012

Öz

Kaynakça

  • Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999 Monani et al., 1999
  • NAIP (Nöral Apoptozis İnhibitör Protein) Genomik uzunluğu 60 kb olan ve 16 ekzonu bulunan NAIP geni; 1232 amino asit uzunluğundaki 140 kD’luk bir proteini kodlar9. NAIP geni 1995 yılında SMA hastalarında delesyona uğrayan ikinci aday gen olarak tespit edilmiştir44. NAIP gen ekspresyonu doku özgüllüğü göstermez. Bu genin bir tam ve birden fazla kesikli kopyası vardır45. Hastalarda sadece tam kopyanın ve 6. ekzonlarında delesyon bulunması28,46nedeniyle delesyon analizi için tam kopyadaki ekzon 5 ve 6’nın multipleks PCR ile amplikasyonu yapılır ve delesyon varlığı araştırılır12.
  • SMA tip I grubunda yapılan 151. kodon ve 3’ucu 1939. nükleotid değişimi analizleri telomerik gende %53.5 oranında homozigot delesyon olduğunu göstermiştir12. Ancak, p44 geninde delesyon bulunduran hastaların tamamında SMN, bir kısmında da SMN ve NAIP genlerinde delesyon olması p44 genindeki mutasyonların hastalığın esas nedeni olmadığını düşündürmüştür. Bugüne kadar sadece p44 gen delesyonu bulunan bir SMA vakasının gösterilememiş olması genin tanı amaçlı olarak kullanılmasını ve önemini azaltmıştır12,27.
  • H4F5 ( SMA Modifiye Edici Gen 1) Scharf ve ark. tarafından 1998’de çok kopyalı mikrosatellit markır (C212) kullanılarak yapılan çalışmada, Tip I hastalarının %90’nında H4F5 gen bölgesinin delesyona uğradığı saptanmıştır. H4F5 geni tek başına SMA hastalığına yol açmazken hastalığın şiddeti üzerine etkili olmaktadır8,26,27.
  • McAndrew PE, Parsons DW, Simard LR, et al.Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. Am J Hum Genet 1997; 60:1411-22.
  • Parsons DW, McAndrew PE, Monani UR, et al. An 11 base pair duplication in exon 6 of the SMN gene produces a type I spinal muscular atrophy (SMA) phenotype: further evidence for SMN as the primary SMA-determining gene. Hum Mol Genet 1996 ; 5:1727-32. http://www.ncbi.nlm.nih.gov/books/NBK1352/ (Erişim tarih:04.2012)
  • Munsat T L. The Spinal Muscular Atrophies. Curr Neurology, 1994;4(3):55-71.
  • Bradley WG, Daroff RB, Fenichel GM, et al. Neurology in Clinical Practice Volume II.3th. Ed., Butterworth Heinemann., 2000; 1997-2004.
  • Brand T, Caplan LR, Dichgans J, et al. Neurological Disorders Course and Treatment. Academic Press USA. 1996; 814-815.
  • Bradley WG, Daroff RB, Fenichel GM, et al. Neurology in Clinical Practice Volume II.3th. Ed., Butterworth Heinemann., 2000; 1997-2004.
  • Rietschel M, Rudnick-Schonborn S, Zerres K. Clinical variability of autosomal dominant spinal muscular atrophy. J Neurol Sci 1992; 107:65-73.
  • Pehlivan s, Topaloğlu H, Erdem H. Centromeric survival motor neuron gene deletion in congenital muscular dystrophy. Balkan Journal of Medical Genetics (BJMG), 1999; (1):4142.
  • Migata M, Uchikoba Y, Orimo H, et al. Genetic diagnosis of Werdnig-Hoffman disease: A problem for application to prenatal diagnosis. J Nippon Med Sch 2003; 70 (1) :45-8. http://tr.wikipedia.org/wiki/Kromozom_5 ( Erişim tarih: 01. 2010) http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603011 (Erişim tarih: 09.2011)
  • Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000; 15:228-37.
  • Wirth B, Tessarolo D, Hahnen E, et al. Different entities of proximal spinal muscular atrophy within one family. Hum Genet 1997; 100:676–80.
  • Wirth B, Herz M, Wetter A, et al. Quantitative Analysis of survival motor neuron copies: ıdentification of subtle smn1 mutations in patients with spinal muscular atrophy, genotype- phenotype correlation, and ımplications for genetic counseling. Am J Hum Genet 1999; 64: –56. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603011 (Erişim tarih: 09.2011)
  • Zhang HL, Pan F, Hong D, et al. Active transport of the survival motor neuron protein and the role of exon-7 in cytoplasmic localization. J Neurosci, 2003; 23(16): 6627– 37.
  • Strasswimmer J, Lorson CL, Breiding DE ,Chen JJ, Le T, Burghes A, Androphy E. Identification of survival motor neuron as a transcriptional activator-binding protein .Human Mol Genet 1999; 8(7):1219-26.
  • Frugier T, Nicole S, Cifuentes-Diaz C et al. The molecular bases of spinal muscular atropy. Curr Opin Genet Dev 2002; 12:294-98. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600354 ( Erişim tarih: 06.2011)
  • Melki J, Lefebvre S, Burglen L, et al. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science 1994; 264:1474-77.
  • Jablonka S, Rossoll W, Schrank B, et al. The role of SMN in spinal muscular atrophy. J Neurol 2000; 247: 37–42.
  • Semprini S, Tacconellı A, Capon F, et al. A single strand conformation polymorphism-based carrier test for spinal muscular atrophy. Genetıc Testıng, 2001; 5: 33-7.
  • Le TT, Coovert DD, Monani UR, et al. The survival motor neuron (SMN) protein: effect of exon loss and mutation on protein localization. Neurogenetics 2000; 3:7–16.
  • Labrum R, Rodda J, Krause A. The molecular basis of Spinal Muscular Atrophy (SMA) in South African black patients. Neuromuscular Disorders 2007; 17: 684–92.
  • Amara A, Adala L, Charfeddine I B, et al. Correlation of SMN2, NAIP, p44, H4F5 and Occludin genes copy number with spinal muscular atrophy phenotype in Tunisian patients. European journal of Paediatric Neurology, 2012; 16:167 -74.
  • Zat’kova A, Hahnen E, Wirth B, et al. Analysis of the SMN and NAIP genes in Slovak spinal muscular atropy patients. Human Heredity 2000; 50:171-74.
  • Kocatürk-Sel S, Kasap H,Koç F. Spinal Müsküler atrofi hastalarında smn geni ekzon 7 ve ’in moleküler analizi / molecular analysis of exon 7 and 8 of smn gene in spinal muscular atrophy patients. Türk Nöroloji Dergisi 2006;12(5):353-61.
  • Kim CA, Passos-Bueno MR, Marie SK, et al. Clinical and molecular analysis of spinal muscular atrophy ın brazilian patients. Genet Mol Biology 1999; 22(4):487-92.
  • Roy N, Mahadevan MS, McLean M, et al. The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy. Cell 1995; 80:167-78.
  • Velasco E, Valero C, Valero A, et al.. Molecular analysis of the SMN and NAIP genes in Spanish spinal muscular atrophy (SMA) families and correlation between number of copies of cBCD541 and SMA phenotype. Hum Mol Genet 1996; 5:257-63.
  • Akutsu T, Nıshıo H, Sumıno K, et al. Molecular genetics of spinal muscular atrophy: contribution of the NAIP gene to clinical severity. Kobe J Med Sci, 2002; 48: 25-31.
  • Parsons DW, McAndrew PE, Iannaccone ST, et al. Intragenic telSMN Mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number. Am J Hum Genet 1998; 63:1712–23.
  • Desprez DG, Brun T, Rochette C, et al. The SMN genes are subject to transcriptional regulation during cellular differentiation. Gene, 2001; 279: 109- 117.
  • Fallini C, Bassell G J, W Rossolla. Spinal muscular atrophy: The role of SMN in axonal mRNA regulation.Brain Res. 2012 (Article in press)
  • Savaş S, Gokgoz N, Kayserili H, Ozkinay F, Yuksel-Apak M, Kirdar B. Screening of deletions in SMN, NAIP and BTF2p44 genes in Turkish spinal muscular atrophy patiens. Human Heredity , 2000; 50: 162-5.
  • Şimşek M, Bulushı TA, Shanmugakonar M, Barwanı HSA, Bayoumı R. Allele-Specific Amplification of Exon 7 in the Survival Motor Neuron (SMN) Genes for Molecular Diagnosis of Spinal Muscular Atrophy. Genet Testıng, 2003; 7: 325-7.
  • Chang J-G, Jong Y-J, Lin S-P, et al. Molecular analysis of Survival motor neuron (SMN) and neuronal apoptosisi inhibitory protein (NAIP) genes ao spinal muscular atrophy patients and their parents. Hum Genet, 1997;100: 577-81. http://internalmed.wustl.edu/divisions/enzymes/comRM.htm (Erişim tarih: 06.2005)
  • Mailman MD, Heinz JW, Papp AC, et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med, 2002; 4:20-26.
  • De-Maw Chuang, Yan Leng, Zoya Marinova, et al. Multiple roles of HDAC inhibition in neurodegenerative conditions Trends Neurosci. 2009; 32(11): 591–601.
  • Tatar G B, Dayangaç-Erden D, Erdem- Yurter H Spinal musküler atrofi tedavisinde histon deasetilaz inhibitörlerinin rolü. Hacettepe Tıp Dergisi 2010; 41:90-6.
Toplam 40 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Bölüm Derleme
Yazarlar

Sabriye Kocatürk Sel Bu kişi benim

Halil Kasap Bu kişi benim

Filiz Koç Bu kişi benim

Ali İrfan Güzel Bu kişi benim

Yayımlanma Tarihi 1 Mart 2012
Yayımlandığı Sayı Yıl 2012 Cilt: 21 Sayı: 1

Kaynak Göster

AMA Sel SK, Kasap H, Koç F, Güzel Aİ. Spinal Müsküler Atrofi ve Moleküler Genetiği. aktd. Mart 2012;21(1):1-26.