論文 - 詳細
| RRC ID | 76171 |
|---|---|
| 著者 | Fielder SM, Rosenfeld JA, Burrage LC, Emrick L, Lalani S, Attali R, Bembenek JN, Hoang H, Baldridge D, Silverman GA, Undiagnosed Diseases Network, Schedl T, Pak SC. |
| タイトル | Functional analysis of a novel de novo variant in PPP5C associated with microcephaly, seizures, and developmental delay. |
| ジャーナル | Mol Genet Metab |
| Abstract |
We describe a proband evaluated through the Undiagnosed Diseases Network (UDN) who presented with microcephaly, developmental delay, and refractory epilepsy with a de novo p.Ala47Thr missense variant in the protein phosphatase gene, PPP5C. This gene has not previously been associated with a Mendelian disease, and based on the population database, gnomAD, the gene has a low tolerance for loss-of-function variants (pLI = 1, o/e = 0.07). We functionally evaluated the PPP5C variant in C. elegans by knocking the variant into the orthologous gene, pph-5, at the corresponding residue, Ala48Thr. We employed assays in three different biological processes where pph-5 was known to function through opposing the activity of genes, mec-15 and sep-1. We demonstrated that, in contrast to control animals, the pph-5 Ala48Thr variant suppresses the neurite growth phenotype and the GABA signaling defects of mec-15 mutants, and the embryonic lethality of sep-1 mutants. The Ala48Thr variant did not display dominance and behaved similarly to the reference pph-5 null, indicating that the variant is likely a strong hypomorph or complete loss-of-function. We conclude that pph-5 Ala48Thr is damaging in C. elegans. By extension in the proband, PPP5C p.Ala47Thr is likely damaging, the de novo dominant presentation is consistent with haplo-insufficiency, and the PPP5C variant is likely responsible for one or more of the proband's phenotypes. |
| 巻・号 | 136(1) |
| ページ | 65-73 |
| 公開日 | 2022-5-1 |
| DOI | 10.1016/j.ymgme.2022.03.007 |
| PII | S1096-7192(22)00170-6 |
| PMID | 35361529 |
| PMC | PMC10200280 |
| MeSH | Animals Caenorhabditis elegans / genetics Caenorhabditis elegans Proteins / genetics Child Developmental Disabilities* / genetics F-Box Proteins* / genetics Humans Microcephaly* / genetics Mutation, Missense Nuclear Proteins* / genetics Phenotype Phosphoprotein Phosphatases* / genetics Seizures* / genetics Separase / genetics |
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オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 5 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 線虫 | tm2979 |