Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations
ABSTRACT In this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy caused by mutations in the small heat shock proteins HSPB1 and HSPB8 and investigate the functional consequences of newly discovered variants. Among 510 unrelated patients with distal motor neuropathy,...
Gespeichert in:
| Veröffentlicht in: | Human mutation 2017-05, Vol.38 (5), p.556-568 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 568 |
|---|---|
| container_issue | 5 |
| container_start_page | 556 |
| container_title | Human mutation |
| container_volume | 38 |
| creator | Echaniz‐Laguna, Andoni Geuens, Thomas Petiot, Philippe Péréon, Yann Adriaenssens, Elias Haidar, Mansour Capponi, Simona Maisonobe, Thierry Fournier, Emmanuel Dubourg, Odile Degos, Bertrand Salachas, François Lenglet, Timothée Eymard, Bruno Delmont, Emilien Pouget, Jean Juntas Morales, Raul Goizet, Cyril Latour, Philippe Timmerman, Vincent Stojkovic, Tanya |
| description | ABSTRACT
In this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy caused by mutations in the small heat shock proteins HSPB1 and HSPB8 and investigate the functional consequences of newly discovered variants. Among 510 unrelated patients with distal motor neuropathy, we identified mutations in HSPB1 (28 index patients/510; 5.5%) and HSPB8 (four index patients/510; 0.8%) genes. Patients have slowly progressive distal (100%) and proximal (13%) weakness in lower limbs (100%), mild lower limbs sensory involvement (31%), foot deformities (73%), progressive distal upper limb weakness (29%), mildly raised serum creatine kinase levels (100%), and central nervous system involvement (9%). We identified 12 HSPB1 and four HSPB8 mutations, including five and three not previously reported. Transmission was either dominant (78%), recessive (3%), or de novo (19%). Three missense mutations in HSPB1 (Pro7Ser, Gly53Asp, and Gln128Arg) cause hyperphosphorylation of neurofilaments, whereas the C‐terminal mutant Ser187Leu triggers protein aggregation. Two frameshift mutations (Leu58fs and Ala61fs) create a premature stop codon leading to proteasomal degradation. Two mutations in HSPB8 (Lys141Met/Asn) exhibited increased binding to Bag3. We demonstrate that HSPB1 and HSPB8 mutations are a major cause of inherited motor axonal neuropathy. Mutations lead to diverse functional outcomes further demonstrating the pleotropic character of small heat shock proteins.
We report a clinical and genetic study of a cohort of 510 unrelated patients with hereditary axonal neuropathies. In 45 patients we identified mutations in the small heat shock proteins HSPB1 and HSPB8. To understand the consequences of these mutations we performed functional studies of five HSPB1 and three HSPB8 mutations that have not been reported previously. The diverse biological outcomes demonstrate the multifunctional character of small heat shock proteins in health and disease. |
| doi_str_mv | 10.1002/humu.23189 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1897389779</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1863698134</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4549-1e2323b3b5475c4db0c27c777a231d8357ec544482718806b4411f5eaaad4cca3</originalsourceid><addsrcrecordid>eNqNkU9rFDEYh4MotlYvfgAJeBHp1PydJN7KYruFtgp1z0Mmk3VTM8l2kqi9-snNdKuCh-LhJS_hyQO__AB4idERRoi825SxHBGKpXoE9jFSsqnX7PG8c9UIodgeeJbSNUJIck6fgj0iMWNK8X3w8_hHDNrDS1umuNV542yCQ7EwR3hRss4uhgRdgFej9h4urc7wahPNV_hpitm6kN7DhXfBGe0P4akNNjtzCHUY4EkJZn5e7WchuS-bPIuq9zJ-s_6v_Tl4stY-2Rf35wFYnXz4vFg25x9PzxbH541hnKkGW0IJ7WnPmeCGDT0yRBghhK7RB0m5sIYzxiQRWErU9oxhvOZWaz0wYzQ9AG923u0Ub4pNuRtdMtZ7HWwsqav_J2gdof4DbWmrJKasoq__Qa9jmWroOyFHbUsJeZiqWMsFaSv1dkeZKaY02XW3ndyop9sOo26uupur7u6qrvCre2XpRzv8QX93WwG8A747b28fUHXL1cVqJ_0Fmcmydg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1889565726</pqid></control><display><type>article</type><title>Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations</title><source>MEDLINE</source><source>Access via Wiley Online Library</source><creator>Echaniz‐Laguna, Andoni ; Geuens, Thomas ; Petiot, Philippe ; Péréon, Yann ; Adriaenssens, Elias ; Haidar, Mansour ; Capponi, Simona ; Maisonobe, Thierry ; Fournier, Emmanuel ; Dubourg, Odile ; Degos, Bertrand ; Salachas, François ; Lenglet, Timothée ; Eymard, Bruno ; Delmont, Emilien ; Pouget, Jean ; Juntas Morales, Raul ; Goizet, Cyril ; Latour, Philippe ; Timmerman, Vincent ; Stojkovic, Tanya</creator><creatorcontrib>Echaniz‐Laguna, Andoni ; Geuens, Thomas ; Petiot, Philippe ; Péréon, Yann ; Adriaenssens, Elias ; Haidar, Mansour ; Capponi, Simona ; Maisonobe, Thierry ; Fournier, Emmanuel ; Dubourg, Odile ; Degos, Bertrand ; Salachas, François ; Lenglet, Timothée ; Eymard, Bruno ; Delmont, Emilien ; Pouget, Jean ; Juntas Morales, Raul ; Goizet, Cyril ; Latour, Philippe ; Timmerman, Vincent ; Stojkovic, Tanya</creatorcontrib><description>ABSTRACT
In this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy caused by mutations in the small heat shock proteins HSPB1 and HSPB8 and investigate the functional consequences of newly discovered variants. Among 510 unrelated patients with distal motor neuropathy, we identified mutations in HSPB1 (28 index patients/510; 5.5%) and HSPB8 (four index patients/510; 0.8%) genes. Patients have slowly progressive distal (100%) and proximal (13%) weakness in lower limbs (100%), mild lower limbs sensory involvement (31%), foot deformities (73%), progressive distal upper limb weakness (29%), mildly raised serum creatine kinase levels (100%), and central nervous system involvement (9%). We identified 12 HSPB1 and four HSPB8 mutations, including five and three not previously reported. Transmission was either dominant (78%), recessive (3%), or de novo (19%). Three missense mutations in HSPB1 (Pro7Ser, Gly53Asp, and Gln128Arg) cause hyperphosphorylation of neurofilaments, whereas the C‐terminal mutant Ser187Leu triggers protein aggregation. Two frameshift mutations (Leu58fs and Ala61fs) create a premature stop codon leading to proteasomal degradation. Two mutations in HSPB8 (Lys141Met/Asn) exhibited increased binding to Bag3. We demonstrate that HSPB1 and HSPB8 mutations are a major cause of inherited motor axonal neuropathy. Mutations lead to diverse functional outcomes further demonstrating the pleotropic character of small heat shock proteins.
We report a clinical and genetic study of a cohort of 510 unrelated patients with hereditary axonal neuropathies. In 45 patients we identified mutations in the small heat shock proteins HSPB1 and HSPB8. To understand the consequences of these mutations we performed functional studies of five HSPB1 and three HSPB8 mutations that have not been reported previously. The diverse biological outcomes demonstrate the multifunctional character of small heat shock proteins in health and disease.</description><identifier>ISSN: 1059-7794</identifier><identifier>EISSN: 1098-1004</identifier><identifier>DOI: 10.1002/humu.23189</identifier><identifier>PMID: 28144995</identifier><language>eng</language><publisher>United States: Hindawi Limited</publisher><subject>Adolescent ; Adult ; Alleles ; Amino Acid Substitution ; Biomarkers ; Cell Line ; Central nervous system ; Child ; Creatine ; Creatine kinase ; distal hereditary motor neuropathy ; DNA Mutational Analysis ; Feet ; Female ; functional validation of novel mutations ; Gene Frequency ; Genetic Association Studies ; Genotype ; Heat shock proteins ; Heat-Shock Proteins - genetics ; Heat-Shock Proteins, Small - genetics ; HSP27 Heat-Shock Proteins - genetics ; Humans ; Limbs ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Missense mutation ; Motor Neuron Disease - diagnosis ; Motor Neuron Disease - genetics ; Motor task performance ; Multigene Family ; Mutation ; Neurofilaments ; Neuropathy ; Nonsense mutation ; peripheral neuropathies ; Phenotype ; Phosphorylation ; Proteasomes ; Protein interaction ; Protein-Serine-Threonine Kinases - genetics ; Small heat shock proteins ; Stop codon ; Young Adult</subject><ispartof>Human mutation, 2017-05, Vol.38 (5), p.556-568</ispartof><rights>2017 Wiley Periodicals, Inc.</rights><rights>Copyright © 2017 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4549-1e2323b3b5475c4db0c27c777a231d8357ec544482718806b4411f5eaaad4cca3</citedby><cites>FETCH-LOGICAL-c4549-1e2323b3b5475c4db0c27c777a231d8357ec544482718806b4411f5eaaad4cca3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhumu.23189$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhumu.23189$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,781,785,1418,27929,27930,45579,45580</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28144995$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Echaniz‐Laguna, Andoni</creatorcontrib><creatorcontrib>Geuens, Thomas</creatorcontrib><creatorcontrib>Petiot, Philippe</creatorcontrib><creatorcontrib>Péréon, Yann</creatorcontrib><creatorcontrib>Adriaenssens, Elias</creatorcontrib><creatorcontrib>Haidar, Mansour</creatorcontrib><creatorcontrib>Capponi, Simona</creatorcontrib><creatorcontrib>Maisonobe, Thierry</creatorcontrib><creatorcontrib>Fournier, Emmanuel</creatorcontrib><creatorcontrib>Dubourg, Odile</creatorcontrib><creatorcontrib>Degos, Bertrand</creatorcontrib><creatorcontrib>Salachas, François</creatorcontrib><creatorcontrib>Lenglet, Timothée</creatorcontrib><creatorcontrib>Eymard, Bruno</creatorcontrib><creatorcontrib>Delmont, Emilien</creatorcontrib><creatorcontrib>Pouget, Jean</creatorcontrib><creatorcontrib>Juntas Morales, Raul</creatorcontrib><creatorcontrib>Goizet, Cyril</creatorcontrib><creatorcontrib>Latour, Philippe</creatorcontrib><creatorcontrib>Timmerman, Vincent</creatorcontrib><creatorcontrib>Stojkovic, Tanya</creatorcontrib><title>Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations</title><title>Human mutation</title><addtitle>Hum Mutat</addtitle><description>ABSTRACT
In this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy caused by mutations in the small heat shock proteins HSPB1 and HSPB8 and investigate the functional consequences of newly discovered variants. Among 510 unrelated patients with distal motor neuropathy, we identified mutations in HSPB1 (28 index patients/510; 5.5%) and HSPB8 (four index patients/510; 0.8%) genes. Patients have slowly progressive distal (100%) and proximal (13%) weakness in lower limbs (100%), mild lower limbs sensory involvement (31%), foot deformities (73%), progressive distal upper limb weakness (29%), mildly raised serum creatine kinase levels (100%), and central nervous system involvement (9%). We identified 12 HSPB1 and four HSPB8 mutations, including five and three not previously reported. Transmission was either dominant (78%), recessive (3%), or de novo (19%). Three missense mutations in HSPB1 (Pro7Ser, Gly53Asp, and Gln128Arg) cause hyperphosphorylation of neurofilaments, whereas the C‐terminal mutant Ser187Leu triggers protein aggregation. Two frameshift mutations (Leu58fs and Ala61fs) create a premature stop codon leading to proteasomal degradation. Two mutations in HSPB8 (Lys141Met/Asn) exhibited increased binding to Bag3. We demonstrate that HSPB1 and HSPB8 mutations are a major cause of inherited motor axonal neuropathy. Mutations lead to diverse functional outcomes further demonstrating the pleotropic character of small heat shock proteins.
We report a clinical and genetic study of a cohort of 510 unrelated patients with hereditary axonal neuropathies. In 45 patients we identified mutations in the small heat shock proteins HSPB1 and HSPB8. To understand the consequences of these mutations we performed functional studies of five HSPB1 and three HSPB8 mutations that have not been reported previously. The diverse biological outcomes demonstrate the multifunctional character of small heat shock proteins in health and disease.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Alleles</subject><subject>Amino Acid Substitution</subject><subject>Biomarkers</subject><subject>Cell Line</subject><subject>Central nervous system</subject><subject>Child</subject><subject>Creatine</subject><subject>Creatine kinase</subject><subject>distal hereditary motor neuropathy</subject><subject>DNA Mutational Analysis</subject><subject>Feet</subject><subject>Female</subject><subject>functional validation of novel mutations</subject><subject>Gene Frequency</subject><subject>Genetic Association Studies</subject><subject>Genotype</subject><subject>Heat shock proteins</subject><subject>Heat-Shock Proteins - genetics</subject><subject>Heat-Shock Proteins, Small - genetics</subject><subject>HSP27 Heat-Shock Proteins - genetics</subject><subject>Humans</subject><subject>Limbs</subject><subject>Magnetic Resonance Imaging</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Missense mutation</subject><subject>Motor Neuron Disease - diagnosis</subject><subject>Motor Neuron Disease - genetics</subject><subject>Motor task performance</subject><subject>Multigene Family</subject><subject>Mutation</subject><subject>Neurofilaments</subject><subject>Neuropathy</subject><subject>Nonsense mutation</subject><subject>peripheral neuropathies</subject><subject>Phenotype</subject><subject>Phosphorylation</subject><subject>Proteasomes</subject><subject>Protein interaction</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Small heat shock proteins</subject><subject>Stop codon</subject><subject>Young Adult</subject><issn>1059-7794</issn><issn>1098-1004</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU9rFDEYh4MotlYvfgAJeBHp1PydJN7KYruFtgp1z0Mmk3VTM8l2kqi9-snNdKuCh-LhJS_hyQO__AB4idERRoi825SxHBGKpXoE9jFSsqnX7PG8c9UIodgeeJbSNUJIck6fgj0iMWNK8X3w8_hHDNrDS1umuNV542yCQ7EwR3hRss4uhgRdgFej9h4urc7wahPNV_hpitm6kN7DhXfBGe0P4akNNjtzCHUY4EkJZn5e7WchuS-bPIuq9zJ-s_6v_Tl4stY-2Rf35wFYnXz4vFg25x9PzxbH541hnKkGW0IJ7WnPmeCGDT0yRBghhK7RB0m5sIYzxiQRWErU9oxhvOZWaz0wYzQ9AG923u0Ub4pNuRtdMtZ7HWwsqav_J2gdof4DbWmrJKasoq__Qa9jmWroOyFHbUsJeZiqWMsFaSv1dkeZKaY02XW3ndyop9sOo26uupur7u6qrvCre2XpRzv8QX93WwG8A747b28fUHXL1cVqJ_0Fmcmydg</recordid><startdate>201705</startdate><enddate>201705</enddate><creator>Echaniz‐Laguna, Andoni</creator><creator>Geuens, Thomas</creator><creator>Petiot, Philippe</creator><creator>Péréon, Yann</creator><creator>Adriaenssens, Elias</creator><creator>Haidar, Mansour</creator><creator>Capponi, Simona</creator><creator>Maisonobe, Thierry</creator><creator>Fournier, Emmanuel</creator><creator>Dubourg, Odile</creator><creator>Degos, Bertrand</creator><creator>Salachas, François</creator><creator>Lenglet, Timothée</creator><creator>Eymard, Bruno</creator><creator>Delmont, Emilien</creator><creator>Pouget, Jean</creator><creator>Juntas Morales, Raul</creator><creator>Goizet, Cyril</creator><creator>Latour, Philippe</creator><creator>Timmerman, Vincent</creator><creator>Stojkovic, Tanya</creator><general>Hindawi Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201705</creationdate><title>Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations</title><author>Echaniz‐Laguna, Andoni ; Geuens, Thomas ; Petiot, Philippe ; Péréon, Yann ; Adriaenssens, Elias ; Haidar, Mansour ; Capponi, Simona ; Maisonobe, Thierry ; Fournier, Emmanuel ; Dubourg, Odile ; Degos, Bertrand ; Salachas, François ; Lenglet, Timothée ; Eymard, Bruno ; Delmont, Emilien ; Pouget, Jean ; Juntas Morales, Raul ; Goizet, Cyril ; Latour, Philippe ; Timmerman, Vincent ; Stojkovic, Tanya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4549-1e2323b3b5475c4db0c27c777a231d8357ec544482718806b4411f5eaaad4cca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Alleles</topic><topic>Amino Acid Substitution</topic><topic>Biomarkers</topic><topic>Cell Line</topic><topic>Central nervous system</topic><topic>Child</topic><topic>Creatine</topic><topic>Creatine kinase</topic><topic>distal hereditary motor neuropathy</topic><topic>DNA Mutational Analysis</topic><topic>Feet</topic><topic>Female</topic><topic>functional validation of novel mutations</topic><topic>Gene Frequency</topic><topic>Genetic Association Studies</topic><topic>Genotype</topic><topic>Heat shock proteins</topic><topic>Heat-Shock Proteins - genetics</topic><topic>Heat-Shock Proteins, Small - genetics</topic><topic>HSP27 Heat-Shock Proteins - genetics</topic><topic>Humans</topic><topic>Limbs</topic><topic>Magnetic Resonance Imaging</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Missense mutation</topic><topic>Motor Neuron Disease - diagnosis</topic><topic>Motor Neuron Disease - genetics</topic><topic>Motor task performance</topic><topic>Multigene Family</topic><topic>Mutation</topic><topic>Neurofilaments</topic><topic>Neuropathy</topic><topic>Nonsense mutation</topic><topic>peripheral neuropathies</topic><topic>Phenotype</topic><topic>Phosphorylation</topic><topic>Proteasomes</topic><topic>Protein interaction</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Small heat shock proteins</topic><topic>Stop codon</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Echaniz‐Laguna, Andoni</creatorcontrib><creatorcontrib>Geuens, Thomas</creatorcontrib><creatorcontrib>Petiot, Philippe</creatorcontrib><creatorcontrib>Péréon, Yann</creatorcontrib><creatorcontrib>Adriaenssens, Elias</creatorcontrib><creatorcontrib>Haidar, Mansour</creatorcontrib><creatorcontrib>Capponi, Simona</creatorcontrib><creatorcontrib>Maisonobe, Thierry</creatorcontrib><creatorcontrib>Fournier, Emmanuel</creatorcontrib><creatorcontrib>Dubourg, Odile</creatorcontrib><creatorcontrib>Degos, Bertrand</creatorcontrib><creatorcontrib>Salachas, François</creatorcontrib><creatorcontrib>Lenglet, Timothée</creatorcontrib><creatorcontrib>Eymard, Bruno</creatorcontrib><creatorcontrib>Delmont, Emilien</creatorcontrib><creatorcontrib>Pouget, Jean</creatorcontrib><creatorcontrib>Juntas Morales, Raul</creatorcontrib><creatorcontrib>Goizet, Cyril</creatorcontrib><creatorcontrib>Latour, Philippe</creatorcontrib><creatorcontrib>Timmerman, Vincent</creatorcontrib><creatorcontrib>Stojkovic, Tanya</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Human mutation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Echaniz‐Laguna, Andoni</au><au>Geuens, Thomas</au><au>Petiot, Philippe</au><au>Péréon, Yann</au><au>Adriaenssens, Elias</au><au>Haidar, Mansour</au><au>Capponi, Simona</au><au>Maisonobe, Thierry</au><au>Fournier, Emmanuel</au><au>Dubourg, Odile</au><au>Degos, Bertrand</au><au>Salachas, François</au><au>Lenglet, Timothée</au><au>Eymard, Bruno</au><au>Delmont, Emilien</au><au>Pouget, Jean</au><au>Juntas Morales, Raul</au><au>Goizet, Cyril</au><au>Latour, Philippe</au><au>Timmerman, Vincent</au><au>Stojkovic, Tanya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations</atitle><jtitle>Human mutation</jtitle><addtitle>Hum Mutat</addtitle><date>2017-05</date><risdate>2017</risdate><volume>38</volume><issue>5</issue><spage>556</spage><epage>568</epage><pages>556-568</pages><issn>1059-7794</issn><eissn>1098-1004</eissn><abstract>ABSTRACT
In this study, we describe the phenotypic spectrum of distal hereditary motor neuropathy caused by mutations in the small heat shock proteins HSPB1 and HSPB8 and investigate the functional consequences of newly discovered variants. Among 510 unrelated patients with distal motor neuropathy, we identified mutations in HSPB1 (28 index patients/510; 5.5%) and HSPB8 (four index patients/510; 0.8%) genes. Patients have slowly progressive distal (100%) and proximal (13%) weakness in lower limbs (100%), mild lower limbs sensory involvement (31%), foot deformities (73%), progressive distal upper limb weakness (29%), mildly raised serum creatine kinase levels (100%), and central nervous system involvement (9%). We identified 12 HSPB1 and four HSPB8 mutations, including five and three not previously reported. Transmission was either dominant (78%), recessive (3%), or de novo (19%). Three missense mutations in HSPB1 (Pro7Ser, Gly53Asp, and Gln128Arg) cause hyperphosphorylation of neurofilaments, whereas the C‐terminal mutant Ser187Leu triggers protein aggregation. Two frameshift mutations (Leu58fs and Ala61fs) create a premature stop codon leading to proteasomal degradation. Two mutations in HSPB8 (Lys141Met/Asn) exhibited increased binding to Bag3. We demonstrate that HSPB1 and HSPB8 mutations are a major cause of inherited motor axonal neuropathy. Mutations lead to diverse functional outcomes further demonstrating the pleotropic character of small heat shock proteins.
We report a clinical and genetic study of a cohort of 510 unrelated patients with hereditary axonal neuropathies. In 45 patients we identified mutations in the small heat shock proteins HSPB1 and HSPB8. To understand the consequences of these mutations we performed functional studies of five HSPB1 and three HSPB8 mutations that have not been reported previously. The diverse biological outcomes demonstrate the multifunctional character of small heat shock proteins in health and disease.</abstract><cop>United States</cop><pub>Hindawi Limited</pub><pmid>28144995</pmid><doi>10.1002/humu.23189</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1059-7794 |
| ispartof | Human mutation, 2017-05, Vol.38 (5), p.556-568 |
| issn | 1059-7794 1098-1004 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1897389779 |
| source | MEDLINE; Access via Wiley Online Library |
| subjects | Adolescent Adult Alleles Amino Acid Substitution Biomarkers Cell Line Central nervous system Child Creatine Creatine kinase distal hereditary motor neuropathy DNA Mutational Analysis Feet Female functional validation of novel mutations Gene Frequency Genetic Association Studies Genotype Heat shock proteins Heat-Shock Proteins - genetics Heat-Shock Proteins, Small - genetics HSP27 Heat-Shock Proteins - genetics Humans Limbs Magnetic Resonance Imaging Male Middle Aged Missense mutation Motor Neuron Disease - diagnosis Motor Neuron Disease - genetics Motor task performance Multigene Family Mutation Neurofilaments Neuropathy Nonsense mutation peripheral neuropathies Phenotype Phosphorylation Proteasomes Protein interaction Protein-Serine-Threonine Kinases - genetics Small heat shock proteins Stop codon Young Adult |
| title | Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-14T00%3A42%3A59IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Axonal%20Neuropathies%20due%20to%20Mutations%20in%20Small%20Heat%20Shock%20Proteins:%20Clinical,%20Genetic,%20and%20Functional%20Insights%20into%20Novel%20Mutations&rft.jtitle=Human%20mutation&rft.au=Echaniz%E2%80%90Laguna,%20Andoni&rft.date=2017-05&rft.volume=38&rft.issue=5&rft.spage=556&rft.epage=568&rft.pages=556-568&rft.issn=1059-7794&rft.eissn=1098-1004&rft_id=info:doi/10.1002/humu.23189&rft_dat=%3Cproquest_cross%3E1863698134%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1889565726&rft_id=info:pmid/28144995&rfr_iscdi=true |