Loss-of-function variant in SPIN4 causes an X-linked overgrowth syndrome
Overgrowth syndromes can be caused by pathogenic genetic variants in epigenetic writers, such as DNA and histone methyltransferases. However, no overgrowth disorder has previously been ascribed to variants in a gene that acts primarily as an epigenetic reader. Here, we studied a male individual with...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-05-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.167074 |
| _version_ | 1797634303309381632 |
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| author | Julian C. Lui Jacob Wagner Elaine Zhou Lijin Dong Kevin M. Barnes Youn Hee Jee Jeffrey Baron |
| author_facet | Julian C. Lui Jacob Wagner Elaine Zhou Lijin Dong Kevin M. Barnes Youn Hee Jee Jeffrey Baron |
| author_sort | Julian C. Lui |
| collection | DOAJ |
| description | Overgrowth syndromes can be caused by pathogenic genetic variants in epigenetic writers, such as DNA and histone methyltransferases. However, no overgrowth disorder has previously been ascribed to variants in a gene that acts primarily as an epigenetic reader. Here, we studied a male individual with generalized overgrowth of prenatal onset. Exome sequencing identified a hemizygous frameshift variant in Spindlin 4 (SPIN4), with X-linked inheritance. We found evidence that SPIN4 binds specific histone modifications, promotes canonical WNT signaling, and inhibits cell proliferation in vitro and that the identified frameshift variant had lost all of these functions. Ablation of Spin4 in mice recapitulated the human phenotype with generalized overgrowth, including increased longitudinal bone growth. Growth plate analysis revealed increased cell proliferation in the proliferative zone and an increased number of progenitor chondrocytes in the resting zone. We also found evidence of decreased canonical Wnt signaling in growth plate chondrocytes, providing a potential explanation for the increased number of resting zone chondrocytes. Taken together, our findings provide strong evidence that SPIN4 is an epigenetic reader that negatively regulates mammalian body growth and that loss of SPIN4 causes an overgrowth syndrome in humans, expanding our knowledge of the epigenetic regulation of human growth. |
| first_indexed | 2024-03-11T12:05:42Z |
| format | Article |
| id | doaj.art-7cb28f5d0b99487daa54b3d5c0a7b96b |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:42Z |
| publishDate | 2023-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-7cb28f5d0b99487daa54b3d5c0a7b96b2023-11-07T16:25:35ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-05-0189Loss-of-function variant in SPIN4 causes an X-linked overgrowth syndromeJulian C. LuiJacob WagnerElaine ZhouLijin DongKevin M. BarnesYoun Hee JeeJeffrey BaronOvergrowth syndromes can be caused by pathogenic genetic variants in epigenetic writers, such as DNA and histone methyltransferases. However, no overgrowth disorder has previously been ascribed to variants in a gene that acts primarily as an epigenetic reader. Here, we studied a male individual with generalized overgrowth of prenatal onset. Exome sequencing identified a hemizygous frameshift variant in Spindlin 4 (SPIN4), with X-linked inheritance. We found evidence that SPIN4 binds specific histone modifications, promotes canonical WNT signaling, and inhibits cell proliferation in vitro and that the identified frameshift variant had lost all of these functions. Ablation of Spin4 in mice recapitulated the human phenotype with generalized overgrowth, including increased longitudinal bone growth. Growth plate analysis revealed increased cell proliferation in the proliferative zone and an increased number of progenitor chondrocytes in the resting zone. We also found evidence of decreased canonical Wnt signaling in growth plate chondrocytes, providing a potential explanation for the increased number of resting zone chondrocytes. Taken together, our findings provide strong evidence that SPIN4 is an epigenetic reader that negatively regulates mammalian body growth and that loss of SPIN4 causes an overgrowth syndrome in humans, expanding our knowledge of the epigenetic regulation of human growth.https://doi.org/10.1172/jci.insight.167074DevelopmentGenetics |
| spellingShingle | Julian C. Lui Jacob Wagner Elaine Zhou Lijin Dong Kevin M. Barnes Youn Hee Jee Jeffrey Baron Loss-of-function variant in SPIN4 causes an X-linked overgrowth syndrome JCI Insight Development Genetics |
| title | Loss-of-function variant in SPIN4 causes an X-linked overgrowth syndrome |
| title_full | Loss-of-function variant in SPIN4 causes an X-linked overgrowth syndrome |
| title_fullStr | Loss-of-function variant in SPIN4 causes an X-linked overgrowth syndrome |
| title_full_unstemmed | Loss-of-function variant in SPIN4 causes an X-linked overgrowth syndrome |
| title_short | Loss-of-function variant in SPIN4 causes an X-linked overgrowth syndrome |
| title_sort | loss of function variant in spin4 causes an x linked overgrowth syndrome |
| topic | Development Genetics |
| url | https://doi.org/10.1172/jci.insight.167074 |
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