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A primary microcephaly-associated sas-6 mutation perturbs centrosome duplication, dendrite morphogenesis, and ciliogenesis in Caenorhabditis elegans
Abstract The human SASS6(I62T) missense mutation has been linked with the incidence of primary microcephaly in a Pakistani family, although the mechanisms by which this mutation causes disease remain unclear. The SASS6(I62T) mutation corresponds to SAS-6(L69T) in Caenorhabditis elegans. Given that S...
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| Published in: | Genetics (Austin) 2023-08, Vol.224 (4) |
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| creator | Bergwell, Mary Smith, Amy Smith, Ellie Dierlam, Carter Duran, Ramon Haastrup, Erin Napier-Jameson, Rebekah Seidel, Rory Potter, William Norris, Adam Iyer, Jyoti |
| description | Abstract
The human SASS6(I62T) missense mutation has been linked with the incidence of primary microcephaly in a Pakistani family, although the mechanisms by which this mutation causes disease remain unclear. The SASS6(I62T) mutation corresponds to SAS-6(L69T) in Caenorhabditis elegans. Given that SAS-6 is highly conserved, we modeled this mutation in C. elegans and examined the sas-6(L69T) effect on centrosome duplication, ciliogenesis, and dendrite morphogenesis. Our studies revealed that all the above processes are perturbed by the sas-6(L69T) mutation. Specifically, C. elegans carrying the sas-6(L69T) mutation exhibit an increased failure of centrosome duplication in a sensitized genetic background. Further, worms carrying this mutation also display shortened phasmid cilia, an abnormal phasmid cilia morphology, shorter phasmid dendrites, and chemotaxis defects. Our data show that the centrosome duplication defects caused by this mutation are only uncovered in a sensitized genetic background, indicating that these defects are mild. However, the ciliogenesis and dendritic defects caused by this mutation are evident in an otherwise wild-type background, indicating that they are stronger defects. Thus, our studies shed light on the novel mechanisms by which the sas-6(L69T) mutation could contribute to the incidence of primary microcephaly in humans.
Bergwell, Smith et al. reveal that a primary microcephaly-associated sas-6(L69T) mutation affects centrosome duplication, dendrite morphogenesis, and ciliogenesis in C. elegans. The authors show that worms carrying the sas-6(L69T) mutation exhibit mild defects in centrosome duplication and stronger defects in ciliogenesis and dendrite extension; phasmid cilia and dendrite length, cilia morphology, and chemotaxis are all defective in sas-6(L69T) mutant worms. Their results shed light on the possible mechanisms by which this mutation could contribute to primary microcephaly in humans. |
| doi_str_mv | 10.1093/genetics/iyad105 |
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The human SASS6(I62T) missense mutation has been linked with the incidence of primary microcephaly in a Pakistani family, although the mechanisms by which this mutation causes disease remain unclear. The SASS6(I62T) mutation corresponds to SAS-6(L69T) in Caenorhabditis elegans. Given that SAS-6 is highly conserved, we modeled this mutation in C. elegans and examined the sas-6(L69T) effect on centrosome duplication, ciliogenesis, and dendrite morphogenesis. Our studies revealed that all the above processes are perturbed by the sas-6(L69T) mutation. Specifically, C. elegans carrying the sas-6(L69T) mutation exhibit an increased failure of centrosome duplication in a sensitized genetic background. Further, worms carrying this mutation also display shortened phasmid cilia, an abnormal phasmid cilia morphology, shorter phasmid dendrites, and chemotaxis defects. Our data show that the centrosome duplication defects caused by this mutation are only uncovered in a sensitized genetic background, indicating that these defects are mild. However, the ciliogenesis and dendritic defects caused by this mutation are evident in an otherwise wild-type background, indicating that they are stronger defects. Thus, our studies shed light on the novel mechanisms by which the sas-6(L69T) mutation could contribute to the incidence of primary microcephaly in humans.
Bergwell, Smith et al. reveal that a primary microcephaly-associated sas-6(L69T) mutation affects centrosome duplication, dendrite morphogenesis, and ciliogenesis in C. elegans. The authors show that worms carrying the sas-6(L69T) mutation exhibit mild defects in centrosome duplication and stronger defects in ciliogenesis and dendrite extension; phasmid cilia and dendrite length, cilia morphology, and chemotaxis are all defective in sas-6(L69T) mutant worms. Their results shed light on the possible mechanisms by which this mutation could contribute to primary microcephaly in humans.</description><identifier>ISSN: 1943-2631</identifier><identifier>ISSN: 0016-6731</identifier><identifier>EISSN: 1943-2631</identifier><identifier>DOI: 10.1093/genetics/iyad105</identifier><identifier>PMID: 37279547</identifier><language>eng</language><publisher>US: Oxford University Press</publisher><subject>Animals ; Caenorhabditis elegans ; Caenorhabditis elegans - genetics ; Caenorhabditis elegans Proteins - genetics ; Cell Cycle Proteins - genetics ; Centrioles - genetics ; Centrosome ; Chemotaxis ; Cilia ; Defects ; Dendrites ; Genetic Models of Rare Diseases ; Humans ; Microcephaly ; Microcephaly - genetics ; Microencephaly ; Missense mutation ; Morphogenesis ; Morphogenesis - genetics ; Mutation ; Nematodes</subject><ispartof>Genetics (Austin), 2023-08, Vol.224 (4)</ispartof><rights>The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America. 2023</rights><rights>The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c461t-b951e016031288fbaf28ad347cad80dc0f3c62f81ead81c87295276896a26cc73</citedby><cites>FETCH-LOGICAL-c461t-b951e016031288fbaf28ad347cad80dc0f3c62f81ead81c87295276896a26cc73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,1591,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37279547$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Goldstein, B</contributor><creatorcontrib>Bergwell, Mary</creatorcontrib><creatorcontrib>Smith, Amy</creatorcontrib><creatorcontrib>Smith, Ellie</creatorcontrib><creatorcontrib>Dierlam, Carter</creatorcontrib><creatorcontrib>Duran, Ramon</creatorcontrib><creatorcontrib>Haastrup, Erin</creatorcontrib><creatorcontrib>Napier-Jameson, Rebekah</creatorcontrib><creatorcontrib>Seidel, Rory</creatorcontrib><creatorcontrib>Potter, William</creatorcontrib><creatorcontrib>Norris, Adam</creatorcontrib><creatorcontrib>Iyer, Jyoti</creatorcontrib><title>A primary microcephaly-associated sas-6 mutation perturbs centrosome duplication, dendrite morphogenesis, and ciliogenesis in Caenorhabditis elegans</title><title>Genetics (Austin)</title><addtitle>Genetics</addtitle><description>Abstract
The human SASS6(I62T) missense mutation has been linked with the incidence of primary microcephaly in a Pakistani family, although the mechanisms by which this mutation causes disease remain unclear. The SASS6(I62T) mutation corresponds to SAS-6(L69T) in Caenorhabditis elegans. Given that SAS-6 is highly conserved, we modeled this mutation in C. elegans and examined the sas-6(L69T) effect on centrosome duplication, ciliogenesis, and dendrite morphogenesis. Our studies revealed that all the above processes are perturbed by the sas-6(L69T) mutation. Specifically, C. elegans carrying the sas-6(L69T) mutation exhibit an increased failure of centrosome duplication in a sensitized genetic background. Further, worms carrying this mutation also display shortened phasmid cilia, an abnormal phasmid cilia morphology, shorter phasmid dendrites, and chemotaxis defects. Our data show that the centrosome duplication defects caused by this mutation are only uncovered in a sensitized genetic background, indicating that these defects are mild. However, the ciliogenesis and dendritic defects caused by this mutation are evident in an otherwise wild-type background, indicating that they are stronger defects. Thus, our studies shed light on the novel mechanisms by which the sas-6(L69T) mutation could contribute to the incidence of primary microcephaly in humans.
Bergwell, Smith et al. reveal that a primary microcephaly-associated sas-6(L69T) mutation affects centrosome duplication, dendrite morphogenesis, and ciliogenesis in C. elegans. The authors show that worms carrying the sas-6(L69T) mutation exhibit mild defects in centrosome duplication and stronger defects in ciliogenesis and dendrite extension; phasmid cilia and dendrite length, cilia morphology, and chemotaxis are all defective in sas-6(L69T) mutant worms. Their results shed light on the possible mechanisms by which this mutation could contribute to primary microcephaly in humans.</description><subject>Animals</subject><subject>Caenorhabditis elegans</subject><subject>Caenorhabditis elegans - genetics</subject><subject>Caenorhabditis elegans Proteins - genetics</subject><subject>Cell Cycle Proteins - genetics</subject><subject>Centrioles - genetics</subject><subject>Centrosome</subject><subject>Chemotaxis</subject><subject>Cilia</subject><subject>Defects</subject><subject>Dendrites</subject><subject>Genetic Models of Rare Diseases</subject><subject>Humans</subject><subject>Microcephaly</subject><subject>Microcephaly - genetics</subject><subject>Microencephaly</subject><subject>Missense mutation</subject><subject>Morphogenesis</subject><subject>Morphogenesis - genetics</subject><subject>Mutation</subject><subject>Nematodes</subject><issn>1943-2631</issn><issn>0016-6731</issn><issn>1943-2631</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNqFUU1v1DAQjRCIlsKdE7LEBYmG-iNx7BOqVnxJlbjA2Zq1J7uuEjvYTqX9H_xgst3dqnDhNJ6ZN0_v-VXVa0Y_MKrF1QYDFm_zld-BY7R9Up0z3YiaS8GePnqfVS9yvqWUSt2q59WZ6Hin26Y7r35fkyn5EdKOjN6maHHawrCrIedoPRR0JEOuJRnnAsXHQCZMZU7rTCyGkmKOIxI3T4O39_tL4jC45AuSMaZpG_cas8-XBIIj1g_-NCE-kBVgiGkLa-fLMsEBNxDyy-pZD0PGV8d6Uf38_OnH6mt98_3Lt9X1TW0byUq91i1DyiQVjCvVr6HnCpxoOgtOUWdpL6zkvWK49MyqjuuWd1JpCVxa24mL6uOBd5rXI7p7QzCY44eYCN78vQl-azbxzjDaMNZqtjC8OzKk-GvGXMzos8VhgIBxzoYrLhrdKd0u0Lf_QG_jnMLizwjaUtHJlu0l0QNqySLnhP2DGkbNPnNzytwcM19O3jx28XBwCnkBvD8A4jz9n-4PDnK-7Q</recordid><startdate>20230809</startdate><enddate>20230809</enddate><creator>Bergwell, Mary</creator><creator>Smith, Amy</creator><creator>Smith, Ellie</creator><creator>Dierlam, Carter</creator><creator>Duran, Ramon</creator><creator>Haastrup, Erin</creator><creator>Napier-Jameson, Rebekah</creator><creator>Seidel, Rory</creator><creator>Potter, William</creator><creator>Norris, Adam</creator><creator>Iyer, Jyoti</creator><general>Oxford University Press</general><general>Genetics Society of America</general><scope>TOX</scope><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>4T-</scope><scope>4U-</scope><scope>7QP</scope><scope>7SS</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20230809</creationdate><title>A primary microcephaly-associated sas-6 mutation perturbs centrosome duplication, dendrite morphogenesis, and ciliogenesis in Caenorhabditis elegans</title><author>Bergwell, Mary ; Smith, Amy ; Smith, Ellie ; Dierlam, Carter ; Duran, Ramon ; Haastrup, Erin ; Napier-Jameson, Rebekah ; Seidel, Rory ; Potter, William ; Norris, Adam ; Iyer, Jyoti</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c461t-b951e016031288fbaf28ad347cad80dc0f3c62f81ead81c87295276896a26cc73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Animals</topic><topic>Caenorhabditis elegans</topic><topic>Caenorhabditis elegans - genetics</topic><topic>Caenorhabditis elegans Proteins - genetics</topic><topic>Cell Cycle Proteins - genetics</topic><topic>Centrioles - genetics</topic><topic>Centrosome</topic><topic>Chemotaxis</topic><topic>Cilia</topic><topic>Defects</topic><topic>Dendrites</topic><topic>Genetic Models of Rare Diseases</topic><topic>Humans</topic><topic>Microcephaly</topic><topic>Microcephaly - genetics</topic><topic>Microencephaly</topic><topic>Missense mutation</topic><topic>Morphogenesis</topic><topic>Morphogenesis - genetics</topic><topic>Mutation</topic><topic>Nematodes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bergwell, Mary</creatorcontrib><creatorcontrib>Smith, Amy</creatorcontrib><creatorcontrib>Smith, Ellie</creatorcontrib><creatorcontrib>Dierlam, Carter</creatorcontrib><creatorcontrib>Duran, Ramon</creatorcontrib><creatorcontrib>Haastrup, Erin</creatorcontrib><creatorcontrib>Napier-Jameson, Rebekah</creatorcontrib><creatorcontrib>Seidel, Rory</creatorcontrib><creatorcontrib>Potter, William</creatorcontrib><creatorcontrib>Norris, Adam</creatorcontrib><creatorcontrib>Iyer, Jyoti</creatorcontrib><collection>Open Access: Oxford University Press Open Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Docstoc</collection><collection>University Readers</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genetics (Austin)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bergwell, Mary</au><au>Smith, Amy</au><au>Smith, Ellie</au><au>Dierlam, Carter</au><au>Duran, Ramon</au><au>Haastrup, Erin</au><au>Napier-Jameson, Rebekah</au><au>Seidel, Rory</au><au>Potter, William</au><au>Norris, Adam</au><au>Iyer, Jyoti</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A primary microcephaly-associated sas-6 mutation perturbs centrosome duplication, dendrite morphogenesis, and ciliogenesis in Caenorhabditis elegans</atitle><jtitle>Genetics (Austin)</jtitle><addtitle>Genetics</addtitle><date>2023-08-09</date><risdate>2023</risdate><volume>224</volume><issue>4</issue><issn>1943-2631</issn><issn>0016-6731</issn><eissn>1943-2631</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>Conflicts of interest statement The author(s) declare no conflict of interest.</notes><notes>MB and AS are co-first authors and they contributed equally to this work.</notes><notes>ES and CD are co-second authors and they contributed equally to this work.</notes><abstract>Abstract
The human SASS6(I62T) missense mutation has been linked with the incidence of primary microcephaly in a Pakistani family, although the mechanisms by which this mutation causes disease remain unclear. The SASS6(I62T) mutation corresponds to SAS-6(L69T) in Caenorhabditis elegans. Given that SAS-6 is highly conserved, we modeled this mutation in C. elegans and examined the sas-6(L69T) effect on centrosome duplication, ciliogenesis, and dendrite morphogenesis. Our studies revealed that all the above processes are perturbed by the sas-6(L69T) mutation. Specifically, C. elegans carrying the sas-6(L69T) mutation exhibit an increased failure of centrosome duplication in a sensitized genetic background. Further, worms carrying this mutation also display shortened phasmid cilia, an abnormal phasmid cilia morphology, shorter phasmid dendrites, and chemotaxis defects. Our data show that the centrosome duplication defects caused by this mutation are only uncovered in a sensitized genetic background, indicating that these defects are mild. However, the ciliogenesis and dendritic defects caused by this mutation are evident in an otherwise wild-type background, indicating that they are stronger defects. Thus, our studies shed light on the novel mechanisms by which the sas-6(L69T) mutation could contribute to the incidence of primary microcephaly in humans.
Bergwell, Smith et al. reveal that a primary microcephaly-associated sas-6(L69T) mutation affects centrosome duplication, dendrite morphogenesis, and ciliogenesis in C. elegans. The authors show that worms carrying the sas-6(L69T) mutation exhibit mild defects in centrosome duplication and stronger defects in ciliogenesis and dendrite extension; phasmid cilia and dendrite length, cilia morphology, and chemotaxis are all defective in sas-6(L69T) mutant worms. Their results shed light on the possible mechanisms by which this mutation could contribute to primary microcephaly in humans.</abstract><cop>US</cop><pub>Oxford University Press</pub><pmid>37279547</pmid><doi>10.1093/genetics/iyad105</doi><oa>free_for_read</oa></addata></record> |
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| source | Oxford University Press Journals; Freely Accessible Science Journals - check A-Z of ejournals; Alma/SFX Local Collection |
| subjects | Animals Caenorhabditis elegans Caenorhabditis elegans - genetics Caenorhabditis elegans Proteins - genetics Cell Cycle Proteins - genetics Centrioles - genetics Centrosome Chemotaxis Cilia Defects Dendrites Genetic Models of Rare Diseases Humans Microcephaly Microcephaly - genetics Microencephaly Missense mutation Morphogenesis Morphogenesis - genetics Mutation Nematodes |
| title | A primary microcephaly-associated sas-6 mutation perturbs centrosome duplication, dendrite morphogenesis, and ciliogenesis in Caenorhabditis elegans |
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