Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy

Alessandra Ruggieri, Francesco Brancati, Simona Zanotti, Lorenzo Maggi, Maria Barbara Pasanisi, Simona Saredi, Chiara Terracciano, Carlo Antozzi, Maria Rosaria D Apice, Federica Sangiuolo, Giuseppe Novelli, Christian R. Marshall, Stephen W. Scherer, Lucia Morandi, Luca Federici, Roberto Massa, Marina Mora, Berge A. Minassian

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

INTRODUCTION: Protein aggregation is a common cause of neuropathology. The protein aggregation myopathy Limb-Girdle Muscular Dystrophy 1D (LGMD1D) is caused by mutations of amino acids Phe89 or Phe93 of DNAJB6, a co-chaperone of the HSP70 anti-aggregation protein. Another DNAJB6 mutation, Pro96Arg, was found to cause a distal-onset myopathy in one family.

RESULTS: We detail the mutational, neuropathological, neurophysiological, neurological and radiological features of five new DNAJB6-myopathy families. One has the known Phe93Leu mutation and classic late-onset slowly progressive LGMD1D. Two have different mutations of Phe91 causing a variant childhood-onset severe limb-girdle myopathy. One has a Phe100Val mutation and distal-onset myopathy, unique early bulbar involvement, and a gender-modified wide age-of-onset range. The last has childhood-onset severe distal-onset myopathy and the first non-missense DNAJB6 mutation, c.346 + 5G > A, causing a splicing defect that entirely eliminates DNAJB6's G/F domain (ΔG/F), the domain that harbours all other mutations. Clinical and imaging examinations reveal that muscles considered uninvolved in DNAJB6-myopathy, e.g. lateral gastrocnemii, are affected in our patients with new mutations. Mutational modelling based on the known structure of the bacterial DNAJ2 protein indicates that all past and present mutated residues cluster within 15 Å in the G/F domain and all disturb the interface of this domain with the protein's J domain that confers the interaction with HSP70.

CONCLUSIONS: Our patients expand the phenotypic spectrum of DNAJB6-myopathy and allow tentative genotype-phenotype specifications. Combining with previous studies, the clinical severity spectrum is as follows: ΔG/F and Phe91 mutations, most severe; Phe100, Pro96, Phe89 mutations, intermediate; and Phe93, least severe. As it stands presently, proximal G/F domain mutations (Phe89, Phe91, Phe93) cause proximal limb-girdle myopathy, while distal G/F mutations (Pro96, Phe100) cause distal-onset myopathy. While all mutations affect the G/F-J interaction, each likely does so in different unknown extents or ways. One mutation, ΔG/F, causes its associated severe distal-onset myopathy phenotype in a clear way, through generation of a G/F domain-lacking DNAJB6 protein.

Original languageEnglish (US)
Number of pages1
JournalActa neuropathologica communications
Volume3
DOIs
StatePublished - Jul 25 2015

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Muscular Diseases
Missense Mutation
Distal Myopathies
Mutation
Limb-Girdle Muscular Dystrophies
Proteins
Extremities
Phenotype
Bacterial Proteins
Age of Onset

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy. / Ruggieri, Alessandra; Brancati, Francesco; Zanotti, Simona; Maggi, Lorenzo; Pasanisi, Maria Barbara; Saredi, Simona; Terracciano, Chiara; Antozzi, Carlo; D Apice, Maria Rosaria; Sangiuolo, Federica; Novelli, Giuseppe; Marshall, Christian R.; Scherer, Stephen W.; Morandi, Lucia; Federici, Luca; Massa, Roberto; Mora, Marina; Minassian, Berge A.

In: Acta neuropathologica communications, Vol. 3, 25.07.2015.

Research output: Contribution to journalArticle

Ruggieri, A, Brancati, F, Zanotti, S, Maggi, L, Pasanisi, MB, Saredi, S, Terracciano, C, Antozzi, C, D Apice, MR, Sangiuolo, F, Novelli, G, Marshall, CR, Scherer, SW, Morandi, L, Federici, L, Massa, R, Mora, M & Minassian, BA 2015, 'Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy', Acta neuropathologica communications, vol. 3. https://doi.org/10.1186/s40478-015-0224-0
Ruggieri, Alessandra ; Brancati, Francesco ; Zanotti, Simona ; Maggi, Lorenzo ; Pasanisi, Maria Barbara ; Saredi, Simona ; Terracciano, Chiara ; Antozzi, Carlo ; D Apice, Maria Rosaria ; Sangiuolo, Federica ; Novelli, Giuseppe ; Marshall, Christian R. ; Scherer, Stephen W. ; Morandi, Lucia ; Federici, Luca ; Massa, Roberto ; Mora, Marina ; Minassian, Berge A. / Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy. In: Acta neuropathologica communications. 2015 ; Vol. 3.
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abstract = "INTRODUCTION: Protein aggregation is a common cause of neuropathology. The protein aggregation myopathy Limb-Girdle Muscular Dystrophy 1D (LGMD1D) is caused by mutations of amino acids Phe89 or Phe93 of DNAJB6, a co-chaperone of the HSP70 anti-aggregation protein. Another DNAJB6 mutation, Pro96Arg, was found to cause a distal-onset myopathy in one family.RESULTS: We detail the mutational, neuropathological, neurophysiological, neurological and radiological features of five new DNAJB6-myopathy families. One has the known Phe93Leu mutation and classic late-onset slowly progressive LGMD1D. Two have different mutations of Phe91 causing a variant childhood-onset severe limb-girdle myopathy. One has a Phe100Val mutation and distal-onset myopathy, unique early bulbar involvement, and a gender-modified wide age-of-onset range. The last has childhood-onset severe distal-onset myopathy and the first non-missense DNAJB6 mutation, c.346 + 5G > A, causing a splicing defect that entirely eliminates DNAJB6's G/F domain (ΔG/F), the domain that harbours all other mutations. Clinical and imaging examinations reveal that muscles considered uninvolved in DNAJB6-myopathy, e.g. lateral gastrocnemii, are affected in our patients with new mutations. Mutational modelling based on the known structure of the bacterial DNAJ2 protein indicates that all past and present mutated residues cluster within 15 {\AA} in the G/F domain and all disturb the interface of this domain with the protein's J domain that confers the interaction with HSP70.CONCLUSIONS: Our patients expand the phenotypic spectrum of DNAJB6-myopathy and allow tentative genotype-phenotype specifications. Combining with previous studies, the clinical severity spectrum is as follows: ΔG/F and Phe91 mutations, most severe; Phe100, Pro96, Phe89 mutations, intermediate; and Phe93, least severe. As it stands presently, proximal G/F domain mutations (Phe89, Phe91, Phe93) cause proximal limb-girdle myopathy, while distal G/F mutations (Pro96, Phe100) cause distal-onset myopathy. While all mutations affect the G/F-J interaction, each likely does so in different unknown extents or ways. One mutation, ΔG/F, causes its associated severe distal-onset myopathy phenotype in a clear way, through generation of a G/F domain-lacking DNAJB6 protein.",
author = "Alessandra Ruggieri and Francesco Brancati and Simona Zanotti and Lorenzo Maggi and Pasanisi, {Maria Barbara} and Simona Saredi and Chiara Terracciano and Carlo Antozzi and {D Apice}, {Maria Rosaria} and Federica Sangiuolo and Giuseppe Novelli and Marshall, {Christian R.} and Scherer, {Stephen W.} and Lucia Morandi and Luca Federici and Roberto Massa and Marina Mora and Minassian, {Berge A.}",
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T1 - Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy

AU - Ruggieri, Alessandra

AU - Brancati, Francesco

AU - Zanotti, Simona

AU - Maggi, Lorenzo

AU - Pasanisi, Maria Barbara

AU - Saredi, Simona

AU - Terracciano, Chiara

AU - Antozzi, Carlo

AU - D Apice, Maria Rosaria

AU - Sangiuolo, Federica

AU - Novelli, Giuseppe

AU - Marshall, Christian R.

AU - Scherer, Stephen W.

AU - Morandi, Lucia

AU - Federici, Luca

AU - Massa, Roberto

AU - Mora, Marina

AU - Minassian, Berge A.

PY - 2015/7/25

Y1 - 2015/7/25

N2 - INTRODUCTION: Protein aggregation is a common cause of neuropathology. The protein aggregation myopathy Limb-Girdle Muscular Dystrophy 1D (LGMD1D) is caused by mutations of amino acids Phe89 or Phe93 of DNAJB6, a co-chaperone of the HSP70 anti-aggregation protein. Another DNAJB6 mutation, Pro96Arg, was found to cause a distal-onset myopathy in one family.RESULTS: We detail the mutational, neuropathological, neurophysiological, neurological and radiological features of five new DNAJB6-myopathy families. One has the known Phe93Leu mutation and classic late-onset slowly progressive LGMD1D. Two have different mutations of Phe91 causing a variant childhood-onset severe limb-girdle myopathy. One has a Phe100Val mutation and distal-onset myopathy, unique early bulbar involvement, and a gender-modified wide age-of-onset range. The last has childhood-onset severe distal-onset myopathy and the first non-missense DNAJB6 mutation, c.346 + 5G > A, causing a splicing defect that entirely eliminates DNAJB6's G/F domain (ΔG/F), the domain that harbours all other mutations. Clinical and imaging examinations reveal that muscles considered uninvolved in DNAJB6-myopathy, e.g. lateral gastrocnemii, are affected in our patients with new mutations. Mutational modelling based on the known structure of the bacterial DNAJ2 protein indicates that all past and present mutated residues cluster within 15 Å in the G/F domain and all disturb the interface of this domain with the protein's J domain that confers the interaction with HSP70.CONCLUSIONS: Our patients expand the phenotypic spectrum of DNAJB6-myopathy and allow tentative genotype-phenotype specifications. Combining with previous studies, the clinical severity spectrum is as follows: ΔG/F and Phe91 mutations, most severe; Phe100, Pro96, Phe89 mutations, intermediate; and Phe93, least severe. As it stands presently, proximal G/F domain mutations (Phe89, Phe91, Phe93) cause proximal limb-girdle myopathy, while distal G/F mutations (Pro96, Phe100) cause distal-onset myopathy. While all mutations affect the G/F-J interaction, each likely does so in different unknown extents or ways. One mutation, ΔG/F, causes its associated severe distal-onset myopathy phenotype in a clear way, through generation of a G/F domain-lacking DNAJB6 protein.

AB - INTRODUCTION: Protein aggregation is a common cause of neuropathology. The protein aggregation myopathy Limb-Girdle Muscular Dystrophy 1D (LGMD1D) is caused by mutations of amino acids Phe89 or Phe93 of DNAJB6, a co-chaperone of the HSP70 anti-aggregation protein. Another DNAJB6 mutation, Pro96Arg, was found to cause a distal-onset myopathy in one family.RESULTS: We detail the mutational, neuropathological, neurophysiological, neurological and radiological features of five new DNAJB6-myopathy families. One has the known Phe93Leu mutation and classic late-onset slowly progressive LGMD1D. Two have different mutations of Phe91 causing a variant childhood-onset severe limb-girdle myopathy. One has a Phe100Val mutation and distal-onset myopathy, unique early bulbar involvement, and a gender-modified wide age-of-onset range. The last has childhood-onset severe distal-onset myopathy and the first non-missense DNAJB6 mutation, c.346 + 5G > A, causing a splicing defect that entirely eliminates DNAJB6's G/F domain (ΔG/F), the domain that harbours all other mutations. Clinical and imaging examinations reveal that muscles considered uninvolved in DNAJB6-myopathy, e.g. lateral gastrocnemii, are affected in our patients with new mutations. Mutational modelling based on the known structure of the bacterial DNAJ2 protein indicates that all past and present mutated residues cluster within 15 Å in the G/F domain and all disturb the interface of this domain with the protein's J domain that confers the interaction with HSP70.CONCLUSIONS: Our patients expand the phenotypic spectrum of DNAJB6-myopathy and allow tentative genotype-phenotype specifications. Combining with previous studies, the clinical severity spectrum is as follows: ΔG/F and Phe91 mutations, most severe; Phe100, Pro96, Phe89 mutations, intermediate; and Phe93, least severe. As it stands presently, proximal G/F domain mutations (Phe89, Phe91, Phe93) cause proximal limb-girdle myopathy, while distal G/F mutations (Pro96, Phe100) cause distal-onset myopathy. While all mutations affect the G/F-J interaction, each likely does so in different unknown extents or ways. One mutation, ΔG/F, causes its associated severe distal-onset myopathy phenotype in a clear way, through generation of a G/F domain-lacking DNAJB6 protein.

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