- Email: [email protected]
Interfamilial phenotypic heterogeneity in SMARD1
Neuromuscular Disorders 19 (2009) 193–195
Contents lists available at ScienceDirect
Neuromuscular Disorders journal homepage: www.elsevier.com/locate/nmd
Case report
Interfamilial phenotypic heterogeneity in SMARD1 S. Joseph a,*, S.A. Robb b, S. Mohammed c, S. Lillis c, A. Simonds d, A.Y. Manzur b, S. Walter e, E. Wraige a a
Department of Neurology, Evelina Children’s Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, United Kingdom Genetics Centre, Guys and St. Thomas Hospitals, London, United Kingdom d Academic Department of Sleep Breathing, The Royal Brompton Hospital, London, United Kingdom e The Department of Paediatrics, The Princess Royal Hospital, Farnborough Common, Orpington, Kent, United Kingdom b c
a r t i c l e
i n f o
Article history: Received 15 July 2008 Received in revised form 10 November 2008 Accepted 25 November 2008
Keywords: SMARD1 respiratory distress Hypotonia Muscle weakness IUGR Phenotype IGHMBP2
a b s t r a c t Spinal muscular atrophy with respiratory distress (SMARD1: l-binding protein 2 gene mutation) is characterised by low birth weight, progressive distal limb weakness, diaphragmatic paralysis and subsequent respiratory failure manifesting before 13 months of age. Our case report illustrates marked phenotype variability in two siblings with an identical genetic mutation of SMARD1, one of whom died of fulminant respiratory failure aged 6 months, whereas the other shows limb weakness but, only mild sleep hypoventilation aged 12 years. This suggests other compensatory mechanisms may play a role in modifying SMARD1; broadening our perception of phenotype. Therefore, SMARD1 phenotype should be considered in cases of atypical spinal muscular atrophy even in the absence of overt diaphragmatic weakness. Ó 2008 Elsevier B.V. All rights reserved.
1. Introduction
2. Case report
In 1974 Mellins et al. described two infants with atypical spinal muscular atrophy (SMA) who presented with severe respiratory distress at 1 and 2 months of age respectively [1]. SMA with diaphragmatic involvement was recognised as a clinically distinct disorder in 1997 [2]. By 2005, 45 cases with similar characteristic had been described [3]. Spinal muscular atrophy with type 1 respiratory distress (SMARD1) is an autosomal recessive disorder characterised by low birth weight, progressive distal muscle weakness and lifethreatening respiratory failure due to diaphragmatic dysfunction before 13 months of age [4]. It is caused by homozygous or compound heterozygous mutations in the gene encoding immunoglobulin l-binding protein 2 (IGHMBP2) on chromosome 11q13 [5]. Mutations in this gene have been identified in cases of SMARD1 with both infantile and juvenile onset of respiratory distress [6]. We present two siblings with genetically confirmed SMARD1 displaying extreme phenotypic variability despite apparently identical gene mutations.
2.1. Case 1
* Corresponding author. Address: Royal Hospital for Sick Children, 9 Sciennes Road, Edinburgh EH9 1LF, United Kingdom. Tel.: +44 131 536 0000; fax: +44 131 536 0308. E-mail address: [email protected] (S. Joseph). 0960-8966/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2008.11.013
The first born child of healthy, unrelated parents presented in the second year of life with motor delay. Pregnancy was normal with normal foetal movements and progressed to a normal delivery. Birth weight was 3.23 kg. Early motor development was normal with independent sitting achieved by 6–8 months, crawling at 8 months and pulling to stand and cruising around furniture by 12 months. Subsequent motor development was delayed and she was not able to walk independently until 27 months. Development remained age appropriate in all other domains. Between 19 and 30 months there was progression of predominantly distal weakness with marked muscle wasting and loss of deep tendon reflexes. Early attempts at investigation were rejected by the family but at 35 months she underwent electromyogram which was compatible with active and chronic denervation, nerve conduction studies were normal. Muscle biopsy showed fibre type grouping consistent with neurogenic pathology. Genetic screening for SMN gene deletion was negative. Creatine kinase, thyroid function, ammonia, plasma amino acids, white cell enzymes, very long chain fatty acids, phytanic acid, cerebrospinal fluid protein, cell count and lactate, urine amino and organic acids, cranial and spinal cord magnetic resonance imaging were normal.
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S. Joseph et al. / Neuromuscular Disorders 19 (2009) 193–195
From 4 years of age she had recurrent chest infections; chest radiographs confirmed infective changes with no apparent diaphragmatic abnormality. Overnight oximetry demonstrated mild hypoventilation during rapid eye movement sleep at 7 years but not requiring intervention. Forced expiratory volume (FEV1) and forced vital capacity (FVC) were normal. Feeding difficulties with delayed swallow and poor weight gain were evident by 8 years, necessitating nasogastric tube feeding and ultimately gastrostomy insertion. Since 8 years of age she has retained sufficient power to operate a powered wheelchair. Now aged 13 years she remains clinically stable with no further deterioration in her muscle strength or respiratory function but, has profound muscle weakness affecting proximal and distal muscle groups. 2.2. Case 2 A younger brother was born at term by normal delivery following normal pregnancy. Birth weight 2.8 kg. His cry was noted to be weak from birth. At 4 months he presented with a three week history of cough and two day history of respiratory distress and poor feeding. He was diagnosed with RSV positive bronchiolitis and required intubation and ventilation due to deteriorating respiratory function after forty eight hours. Several attempts at extubation were unsuccessful. Chest radiograph showed an eventration of the right hemi-diaphragm. Weakness, predominantly distal and lower limb, progressed over seven weeks. Deep tendon reflexes, initially preserved, were lost by 5 months of age and he developed tongue fasiculation. Creatine kinase, thyroid function, ammonia, plasma amino acids and urine organic acids were normal. Widespread denervation was evident on EMG and ultrasound confirmed diaphragmatic weakness. Genetic analysis confirmed him to be a compound heterozygote for mutations in IGHMB2 gene associated with SMARD1 (allele 1: missense mutation exon 10 c 1478C > T: p.Thr493ILe Allele 2: stop mutation exon 10 c 1488C > A: p cys 496X). He died of respiratory failure aged 6 months. A diagnosis of SMARD1 was subsequently confirmed genetically in his older sister (case 1), when she was 11 years old. Her three younger sisters, now aged 11, 9 and 4 years, respectively; and both parents remain well. They have declined genetic screening. 3. Discussion SMARD1. is an autosomal recessive disorder due to mutations in IGHMBP2 gene on chromosome 11q13 [5]. The human IGHMBP2 gene has 15 exons [5] and is ubiquitously expressed [7] with the highest levels of IGHMBP2 mRNA detected in the testis and lowmoderate levels detected in other tissues [8]. To date 51 IGHMBP2 gene mutations have been reported [2]. but the precise function of IGHMBP2 and pathophysiological mechanism for disease are unknown [9]. The protein is thought to be involved with immunoglobulin-class switching [7], pre-mRNA processing [10] and regulation of transcription either by DNA binding [11] or by interaction with TATA-binding protein [12]. The prevalence of SMARD is unknown but it has been estimated that 1% of children with early SMA have diaphragmatic paralysis [3]. In the cases described, the c.1488C > A; (p.Cys495X) mutation is predicted to generate a truncated protein molecule which is very likely to be pathogenic. The pathological consequence of the c.1478C > T; (p.Thr492lle) mutation is less clear. However, this amino acid residue is highly conserved in other species and mutation is therefore likely to be pathogenic. Diagnostic criteria for SMARD1 were proposed by Pitt et al in 2003 [13] based on clinical, histopathological and electrophysio-
logical findings in 13 patients with a diagnosis of SMARD1. Proposed clinical criteria were low birth weight, symptom onset within 3 months, diaphragmatic weakness, ventilator dependence within 1 month of onset and absence of other conditions. Histopathological abnormalities on sural nerve biopsy were reduced myelinated fibre size without evidence of regeneration or demyelination. Electrophysiological criteria were evidence of distal denervation and severe slowing of conduction in one or more nerves. Seven of thirteen patients in the series reported by Pitt et al fulfilled all criteria in each category. Case 2 fulfils all of the clinical criteria and this, in conjunction with the genetic findings, allows a diagnosis of SMARD1 to be made in the absence of nerve biopsy. Case 1 does not meet any of the clinical criteria but instead has a later onset disorder with initial progressive muscle weakness and only mild diaphragmatic involvement to date. Muscle weakness was initially distally predominant as described in SMARD1 and extensive investigations failed to identify any other cause for her muscle weakness. Electrophysiology confirmed distal denervation with normal nerve conduction velocities. Nerve biopsy has not been undertaken. The identification of the identical mutations in the IGHMB2 gene to her sibling allows genetic confirmation of SMARD1 despite the atypical clinical presentation. Grohmann et al. [14] have previously reported the case of a child with milder phenotype with no evidence of diaphragmatic involvement until 4 years indicating that juvenile onset SMARD1 can also arise from mutations in IGHMBP2. Additional genetic studies demonstrated that this child had a mutation which caused an in-frame deletion at mRNA level. This was in contrast to an infant with classical SMARD1 who they also investigated and who had a mutation leading to frame shift at the mRNA level. This would therefore be predicted to give rise to a more severe phenotype potentially accounting for the phenotypic heterogeneity in these unrelated children. The siblings we report are of interest because they indicate the potential for phenotypic variability despite carrying an identical genetic mutation predicted to give rise to a truncated protein and hence a severe phenotype. This suggests that other compensatory mechanisms may play a role in modifying the phenotype of SMARD1. The SMARD1 phenotype may be broader than previously appreciated and should be considered in cases of atypical spinal muscular atrophy even in the absence of overt diaphragmatic weakness. Acknowledgement We thank the family of the children described for consenting to publication. References 1 Mellins RB, Hays AP, Gold AP, Berdon WE, Bowdler JD. Respiratory distress as an initial presentation of Werdnig-Hoffman disease. Pediatrics 1974;53:33–40. 2 Rudnik-Schöneborn S, Forkert R, Hahnen E, Wirth B, Zerres K, et al. Clinical spectrum and diagnostic criteria of infantile spinal muscular atrophy: further delineation on the basis of SMN gene deletion findings. Neuropaediatrics 1996;27(1):8–15. 3 Giannini A, Pinto AM, Rossetti G, et al. Respiratory failure in infants due to spinal muscular atrophy with respiratory distress type 1. Intensive Care Med (Italian) 2006;32(11):1851–5. 4 Grohmann K, Varon R, Stolz P, et al. Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Ann Neurol 2003;54(6):719–24. 5 Grohmann K, Schuelke M, Diers A, et al. Mutations in gene coding immunoglobulin binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat Genet 2001;29:75–7. 6 Guenther UP, Schuelke M, Bertinie E, et al. Genomic rearrangements at the IGHMBP2 gene locus in two patients with SMARD1. Hum Genet 2004;115(4):319–26. 7 Fukita Y, Mizuta TR, Shirozu M, Ozawa K, Shimizu A, Honjo T. The Human Slbp2, a DNA-binding protein specific to the single stranded guanine-rich sequence
S. Joseph et al. / Neuromuscular Disorders 19 (2009) 193–195 related to the immunoglobulin l chainswitch region. J Biol Chem 1993;268:17462–70. 8 Mohan WS, Chen ZQ, Zhang X, et al. Human S mu binding protein-2 binds to the drug response element and transactivates the human apo A-I promoter: role of gemfibrozil. J Lipid Res 1998;39:255–67. 9 Maystadt I, Zarhate M, Landrieu P, et al. Allelic heterogeneity of SMARD1 at the IGHMBP2 locus. Hum Mutat 2004;23:525–6. 10 Molnar GM, Crozat A, Kraeft SK, Dou QP, Chen LB, Pardee AB. Association of mammalial helicase MAH with the pre-mRNA splicing complex. Proc Natl Acad Sci (Italian) USA 1997;94:7831–6.
195
11 Chen NN, Kerr D, Chang CF, Honjo T, Khalili K, et al. Evidence for regulation of transcription and replication of human neurotropic virus JCV genome by human Slbp-2 in glial cells. Gene 1997;185:55–62. 12 Zhang Q, Wang YCJ, Montalvo EA. Slbp-2 represses the Epstein-Barr virus lytic switch promoter. Virology 1999;255:160–70. 13 Pitt M, Houlden M, Jacobs J, et al. Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1. Brain 2003;126(12):2682–92. 14 Grohmann K, Wienker TF, Saar K, et al. Diaphragmatic spinal muscular atrophy with respiratory distress is heterogeneous, and one form Is linked to chromosome 11q13-q21. Am J Hum Genet 1999;65(5):1459–62.
Contents lists available at ScienceDirect
Neuromuscular Disorders journal homepage: www.elsevier.com/locate/nmd
Case report
Interfamilial phenotypic heterogeneity in SMARD1 S. Joseph a,*, S.A. Robb b, S. Mohammed c, S. Lillis c, A. Simonds d, A.Y. Manzur b, S. Walter e, E. Wraige a a
Department of Neurology, Evelina Children’s Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom Dubowitz Neuromuscular Centre, Great Ormond Street Hospital for Children, London, United Kingdom Genetics Centre, Guys and St. Thomas Hospitals, London, United Kingdom d Academic Department of Sleep Breathing, The Royal Brompton Hospital, London, United Kingdom e The Department of Paediatrics, The Princess Royal Hospital, Farnborough Common, Orpington, Kent, United Kingdom b c
a r t i c l e
i n f o
Article history: Received 15 July 2008 Received in revised form 10 November 2008 Accepted 25 November 2008
Keywords: SMARD1 respiratory distress Hypotonia Muscle weakness IUGR Phenotype IGHMBP2
a b s t r a c t Spinal muscular atrophy with respiratory distress (SMARD1: l-binding protein 2 gene mutation) is characterised by low birth weight, progressive distal limb weakness, diaphragmatic paralysis and subsequent respiratory failure manifesting before 13 months of age. Our case report illustrates marked phenotype variability in two siblings with an identical genetic mutation of SMARD1, one of whom died of fulminant respiratory failure aged 6 months, whereas the other shows limb weakness but, only mild sleep hypoventilation aged 12 years. This suggests other compensatory mechanisms may play a role in modifying SMARD1; broadening our perception of phenotype. Therefore, SMARD1 phenotype should be considered in cases of atypical spinal muscular atrophy even in the absence of overt diaphragmatic weakness. Ó 2008 Elsevier B.V. All rights reserved.
1. Introduction
2. Case report
In 1974 Mellins et al. described two infants with atypical spinal muscular atrophy (SMA) who presented with severe respiratory distress at 1 and 2 months of age respectively [1]. SMA with diaphragmatic involvement was recognised as a clinically distinct disorder in 1997 [2]. By 2005, 45 cases with similar characteristic had been described [3]. Spinal muscular atrophy with type 1 respiratory distress (SMARD1) is an autosomal recessive disorder characterised by low birth weight, progressive distal muscle weakness and lifethreatening respiratory failure due to diaphragmatic dysfunction before 13 months of age [4]. It is caused by homozygous or compound heterozygous mutations in the gene encoding immunoglobulin l-binding protein 2 (IGHMBP2) on chromosome 11q13 [5]. Mutations in this gene have been identified in cases of SMARD1 with both infantile and juvenile onset of respiratory distress [6]. We present two siblings with genetically confirmed SMARD1 displaying extreme phenotypic variability despite apparently identical gene mutations.
2.1. Case 1
* Corresponding author. Address: Royal Hospital for Sick Children, 9 Sciennes Road, Edinburgh EH9 1LF, United Kingdom. Tel.: +44 131 536 0000; fax: +44 131 536 0308. E-mail address: [email protected] (S. Joseph). 0960-8966/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2008.11.013
The first born child of healthy, unrelated parents presented in the second year of life with motor delay. Pregnancy was normal with normal foetal movements and progressed to a normal delivery. Birth weight was 3.23 kg. Early motor development was normal with independent sitting achieved by 6–8 months, crawling at 8 months and pulling to stand and cruising around furniture by 12 months. Subsequent motor development was delayed and she was not able to walk independently until 27 months. Development remained age appropriate in all other domains. Between 19 and 30 months there was progression of predominantly distal weakness with marked muscle wasting and loss of deep tendon reflexes. Early attempts at investigation were rejected by the family but at 35 months she underwent electromyogram which was compatible with active and chronic denervation, nerve conduction studies were normal. Muscle biopsy showed fibre type grouping consistent with neurogenic pathology. Genetic screening for SMN gene deletion was negative. Creatine kinase, thyroid function, ammonia, plasma amino acids, white cell enzymes, very long chain fatty acids, phytanic acid, cerebrospinal fluid protein, cell count and lactate, urine amino and organic acids, cranial and spinal cord magnetic resonance imaging were normal.
194
S. Joseph et al. / Neuromuscular Disorders 19 (2009) 193–195
From 4 years of age she had recurrent chest infections; chest radiographs confirmed infective changes with no apparent diaphragmatic abnormality. Overnight oximetry demonstrated mild hypoventilation during rapid eye movement sleep at 7 years but not requiring intervention. Forced expiratory volume (FEV1) and forced vital capacity (FVC) were normal. Feeding difficulties with delayed swallow and poor weight gain were evident by 8 years, necessitating nasogastric tube feeding and ultimately gastrostomy insertion. Since 8 years of age she has retained sufficient power to operate a powered wheelchair. Now aged 13 years she remains clinically stable with no further deterioration in her muscle strength or respiratory function but, has profound muscle weakness affecting proximal and distal muscle groups. 2.2. Case 2 A younger brother was born at term by normal delivery following normal pregnancy. Birth weight 2.8 kg. His cry was noted to be weak from birth. At 4 months he presented with a three week history of cough and two day history of respiratory distress and poor feeding. He was diagnosed with RSV positive bronchiolitis and required intubation and ventilation due to deteriorating respiratory function after forty eight hours. Several attempts at extubation were unsuccessful. Chest radiograph showed an eventration of the right hemi-diaphragm. Weakness, predominantly distal and lower limb, progressed over seven weeks. Deep tendon reflexes, initially preserved, were lost by 5 months of age and he developed tongue fasiculation. Creatine kinase, thyroid function, ammonia, plasma amino acids and urine organic acids were normal. Widespread denervation was evident on EMG and ultrasound confirmed diaphragmatic weakness. Genetic analysis confirmed him to be a compound heterozygote for mutations in IGHMB2 gene associated with SMARD1 (allele 1: missense mutation exon 10 c 1478C > T: p.Thr493ILe Allele 2: stop mutation exon 10 c 1488C > A: p cys 496X). He died of respiratory failure aged 6 months. A diagnosis of SMARD1 was subsequently confirmed genetically in his older sister (case 1), when she was 11 years old. Her three younger sisters, now aged 11, 9 and 4 years, respectively; and both parents remain well. They have declined genetic screening. 3. Discussion SMARD1. is an autosomal recessive disorder due to mutations in IGHMBP2 gene on chromosome 11q13 [5]. The human IGHMBP2 gene has 15 exons [5] and is ubiquitously expressed [7] with the highest levels of IGHMBP2 mRNA detected in the testis and lowmoderate levels detected in other tissues [8]. To date 51 IGHMBP2 gene mutations have been reported [2]. but the precise function of IGHMBP2 and pathophysiological mechanism for disease are unknown [9]. The protein is thought to be involved with immunoglobulin-class switching [7], pre-mRNA processing [10] and regulation of transcription either by DNA binding [11] or by interaction with TATA-binding protein [12]. The prevalence of SMARD is unknown but it has been estimated that 1% of children with early SMA have diaphragmatic paralysis [3]. In the cases described, the c.1488C > A; (p.Cys495X) mutation is predicted to generate a truncated protein molecule which is very likely to be pathogenic. The pathological consequence of the c.1478C > T; (p.Thr492lle) mutation is less clear. However, this amino acid residue is highly conserved in other species and mutation is therefore likely to be pathogenic. Diagnostic criteria for SMARD1 were proposed by Pitt et al in 2003 [13] based on clinical, histopathological and electrophysio-
logical findings in 13 patients with a diagnosis of SMARD1. Proposed clinical criteria were low birth weight, symptom onset within 3 months, diaphragmatic weakness, ventilator dependence within 1 month of onset and absence of other conditions. Histopathological abnormalities on sural nerve biopsy were reduced myelinated fibre size without evidence of regeneration or demyelination. Electrophysiological criteria were evidence of distal denervation and severe slowing of conduction in one or more nerves. Seven of thirteen patients in the series reported by Pitt et al fulfilled all criteria in each category. Case 2 fulfils all of the clinical criteria and this, in conjunction with the genetic findings, allows a diagnosis of SMARD1 to be made in the absence of nerve biopsy. Case 1 does not meet any of the clinical criteria but instead has a later onset disorder with initial progressive muscle weakness and only mild diaphragmatic involvement to date. Muscle weakness was initially distally predominant as described in SMARD1 and extensive investigations failed to identify any other cause for her muscle weakness. Electrophysiology confirmed distal denervation with normal nerve conduction velocities. Nerve biopsy has not been undertaken. The identification of the identical mutations in the IGHMB2 gene to her sibling allows genetic confirmation of SMARD1 despite the atypical clinical presentation. Grohmann et al. [14] have previously reported the case of a child with milder phenotype with no evidence of diaphragmatic involvement until 4 years indicating that juvenile onset SMARD1 can also arise from mutations in IGHMBP2. Additional genetic studies demonstrated that this child had a mutation which caused an in-frame deletion at mRNA level. This was in contrast to an infant with classical SMARD1 who they also investigated and who had a mutation leading to frame shift at the mRNA level. This would therefore be predicted to give rise to a more severe phenotype potentially accounting for the phenotypic heterogeneity in these unrelated children. The siblings we report are of interest because they indicate the potential for phenotypic variability despite carrying an identical genetic mutation predicted to give rise to a truncated protein and hence a severe phenotype. This suggests that other compensatory mechanisms may play a role in modifying the phenotype of SMARD1. The SMARD1 phenotype may be broader than previously appreciated and should be considered in cases of atypical spinal muscular atrophy even in the absence of overt diaphragmatic weakness. Acknowledgement We thank the family of the children described for consenting to publication. References 1 Mellins RB, Hays AP, Gold AP, Berdon WE, Bowdler JD. Respiratory distress as an initial presentation of Werdnig-Hoffman disease. Pediatrics 1974;53:33–40. 2 Rudnik-Schöneborn S, Forkert R, Hahnen E, Wirth B, Zerres K, et al. Clinical spectrum and diagnostic criteria of infantile spinal muscular atrophy: further delineation on the basis of SMN gene deletion findings. Neuropaediatrics 1996;27(1):8–15. 3 Giannini A, Pinto AM, Rossetti G, et al. Respiratory failure in infants due to spinal muscular atrophy with respiratory distress type 1. Intensive Care Med (Italian) 2006;32(11):1851–5. 4 Grohmann K, Varon R, Stolz P, et al. Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1). Ann Neurol 2003;54(6):719–24. 5 Grohmann K, Schuelke M, Diers A, et al. Mutations in gene coding immunoglobulin binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat Genet 2001;29:75–7. 6 Guenther UP, Schuelke M, Bertinie E, et al. Genomic rearrangements at the IGHMBP2 gene locus in two patients with SMARD1. Hum Genet 2004;115(4):319–26. 7 Fukita Y, Mizuta TR, Shirozu M, Ozawa K, Shimizu A, Honjo T. The Human Slbp2, a DNA-binding protein specific to the single stranded guanine-rich sequence
S. Joseph et al. / Neuromuscular Disorders 19 (2009) 193–195 related to the immunoglobulin l chainswitch region. J Biol Chem 1993;268:17462–70. 8 Mohan WS, Chen ZQ, Zhang X, et al. Human S mu binding protein-2 binds to the drug response element and transactivates the human apo A-I promoter: role of gemfibrozil. J Lipid Res 1998;39:255–67. 9 Maystadt I, Zarhate M, Landrieu P, et al. Allelic heterogeneity of SMARD1 at the IGHMBP2 locus. Hum Mutat 2004;23:525–6. 10 Molnar GM, Crozat A, Kraeft SK, Dou QP, Chen LB, Pardee AB. Association of mammalial helicase MAH with the pre-mRNA splicing complex. Proc Natl Acad Sci (Italian) USA 1997;94:7831–6.
195
11 Chen NN, Kerr D, Chang CF, Honjo T, Khalili K, et al. Evidence for regulation of transcription and replication of human neurotropic virus JCV genome by human Slbp-2 in glial cells. Gene 1997;185:55–62. 12 Zhang Q, Wang YCJ, Montalvo EA. Slbp-2 represses the Epstein-Barr virus lytic switch promoter. Virology 1999;255:160–70. 13 Pitt M, Houlden M, Jacobs J, et al. Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1. Brain 2003;126(12):2682–92. 14 Grohmann K, Wienker TF, Saar K, et al. Diaphragmatic spinal muscular atrophy with respiratory distress is heterogeneous, and one form Is linked to chromosome 11q13-q21. Am J Hum Genet 1999;65(5):1459–62.