{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:01:04Z","timestamp":1792789264640,"version":"4.5.0"},"reference-count":30,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Capital\u2019s Funds for Health Improvement and Research","award":["ShouFa2026-2G-40812"],"award-info":[{"award-number":["ShouFa2026-2G-40812"]}]},{"name":"Research and Development Fund of Peking University People\u2019s Hospital","award":["RS-2025-03"],"award-info":[{"award-number":["RS-2025-03"]}],"id":[{"id":"https:\/\/ror.org\/035adwg89","id-type":"ROR","asserted-by":"crossref"}]},{"award":["RS-2025-03"],"award-info":[{"award-number":["RS-2025-03"]}],"id":[{"id":"https:\/\/ror.org\/035adwg89","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Clinical Medicine Plus X-Young Scholars Project of Peking University, the Fundamental Research Funds for the Central Universities","award":["PKU2023LCXQ042"],"award-info":[{"award-number":["PKU2023LCXQ042"]}]},{"award":["PKU2023LCXQ042"],"award-info":[{"award-number":["PKU2023LCXQ042"]}],"id":[{"id":"https:\/\/ror.org\/02v51f717","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Beijing Natural Science Foundation","doi-asserted-by":"publisher","award":["7232182"],"award-info":[{"award-number":["7232182"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Peking University Clinical Scientist Training Program","award":["BMU2024PYJH016"],"award-info":[{"award-number":["BMU2024PYJH016"]}],"id":[{"id":"https:\/\/ror.org\/02v51f717","id-type":"ROR","asserted-by":"crossref"}]},{"award":["BMU2024PYJH016"],"award-info":[{"award-number":["BMU2024PYJH016"]}],"id":[{"id":"https:\/\/ror.org\/02v51f717","id-type":"ROR","asserted-by":"publisher"}]},{"name":"China Association for Science and Technology: Innovative Service for Management of Scoliosis in Tibetan Adolescents, and the National Key R&D Program of China","award":["2024YFC3308302"],"award-info":[{"award-number":["2024YFC3308302"]}],"id":[{"id":"https:\/\/ror.org\/035vmht26","id-type":"ROR","asserted-by":"crossref"}]},{"award":["2024YFC3308302"],"award-info":[{"award-number":["2024YFC3308302"]}],"id":[{"id":"https:\/\/ror.org\/035vmht26","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background and Objectives: Autosomal recessive cutis laxa (ARCL) is a genetically heterogeneous group of connective-tissue disorders characterized by loose, inelastic skin and variable systemic involvement. Biallelic variants in PYCR1 are associated with PYCR1-related ARCL, including ARCL type IIB (OMIM #612940) and type IIIB (OMIM #614438). We aimed to characterize the clinical and molecular findings in one affected family and provide segregation and variant-specific functional evidence for two previously unreported PYCR1 variants. Methods: The proband and family underwent whole-exome sequencing with copy-number analysis and Sanger confirmation. The splice-site variant was evaluated by qualitative RT-PCR and Sanger sequencing of endogenous peripheral-blood PYCR1 transcripts, whereas the frameshift variant was studied in a heterologous expression system by qPCR and Western blotting. Neuroimaging, exploratory EEG spectral analysis, and public developmental transcriptomic\/single-cell resources were used for complementary phenotypic context. Results: The 16-year-old proband had thin lax skin with prominent superficial veins, generalized joint hypermobility, facial dysmorphism, reduced muscle bulk, and motor developmental delay. Chinese WAIS-IV showed a markedly uneven profile (VCI 52; PRI 94; FSIQ 75). Two previously unreported PYCR1 variants were identified in trans: maternally inherited NM_006907.4:c.139-1G&gt;A and paternally inherited NM_006907.4:c.724_725del, p.(Leu242AlafsTer31). Endogenous RNA analysis identified exon 3 skipping associated with c.139-1G&gt;A (r.139_318del), predicting p.(Met48_Lys107del). The c.724_725del construct showed consistently reduced steady-state abundance of the truncated PYCR1 protein relative to WT across three independent experiments. Both variants were classified as likely pathogenic using the ACMG\/AMP framework with relevant ClinGen refinements. Brain MRI revealed irregular morphology of the anterior corpus callosum. Discussion: These two previously unreported variants extend the PYCR1 variant spectrum and are supported by complementary segregation, RNA-level, and protein-level evidence. The neurodevelopmental observations provide additional phenotypic context and are interpreted descriptively.<\/jats:p>","DOI":"10.3390\/genes17091129","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:50:27Z","timestamp":1789566627000},"page":"1129","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Compound-Heterozygous Variants in PYCR1 Expand the Variant Spectrum of Autosomal Recessive Cutis Laxa"],"prefix":"10.3390","volume":"17","author":[{"given":"Xin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Peking University People\u2019s Hospital, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6999-3117","authenticated-orcid":false,"given":"Zhuran","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University People\u2019s Hospital, Beijing 100044, China"},{"name":"Epilepsy Center, Peking University People\u2019s Hospital, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Weike","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University People\u2019s Hospital, Beijing 100044, China"},{"name":"Epilepsy Center, Peking University People\u2019s Hospital, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Jing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University People\u2019s Hospital, Beijing 100044, China"},{"name":"Epilepsy Center, Peking University People\u2019s Hospital, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Shimin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Peking University People\u2019s Hospital, Beijing 100044, China"},{"name":"Epilepsy Center, Peking University People\u2019s Hospital, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2519-3200","authenticated-orcid":false,"given":"Yanhui","family":"Dong","sequence":"additional","affiliation":[{"name":"National Health Commission Key Laboratory of Reproductive Health, Institute of Child and Adolescent Health, School of Public Health, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3702-4714","authenticated-orcid":false,"given":"Shuai","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Spinal Surgery, Peking University People\u2019s Hospital, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.ajhg.2015.08.001","article-title":"Recurrent de novo mutations affecting residue Arg138 of pyrroline-5-carboxylate synthase cause a progeroid form of autosomal-dominant cutis laxa","volume":"97","author":"Ganesh","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1007\/s10545-011-9411-8","article-title":"Understanding pyrroline-5-carboxylate synthetase deficiency: Clinical, molecular, functional, and expression studies, structure-based analysis, and novel therapy with arginine","volume":"35","author":"Martinelli","year":"2012","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/cge.13865","article-title":"Cutis laxa: A comprehensive overview of clinical characteristics and pathophysiology","volume":"99","author":"Beyens","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_4","first-page":"403","article-title":"Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for ltbp-4 isoforms","volume":"8","author":"Conradi","year":"2015","journal-title":"Dis. Models Mech."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.ymgme.2014.05.003","article-title":"Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1","volume":"112","author":"Fischer","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_6","unstructured":"Gara, S., Riley, C.A., and Litaiem, N. (2025, November 17). Cutis laxa, Statpearls, Available online: http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK532944\/."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1146\/annurev.bi.49.070180.005041","article-title":"Metabolism of proline and the hydroxyprolines","volume":"49","author":"Adams","year":"1980","journal-title":"Annu. Rev. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.ajhg.2009.07.001","article-title":"RIN2 deficiency results in macrocephaly, alopecia, cutis laxa, and scoliosis: MACS syndrome","volume":"85","author":"Sarig","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/978-3-030-80614-9_13","article-title":"Clinical and molecular delineation of cutis laxa syndromes: Paradigms for homeostasis","volume":"1348","author":"Beyens","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1038\/ejhg.2013.154","article-title":"Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa","volume":"22","author":"Gardeitchik","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1038\/ng.413","article-title":"Mutations in PYCR1 cause cutis laxa with progeroid features","volume":"41","author":"Reversade","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.ajhg.2009.06.008","article-title":"Mutation in pyrroline-5-carboxylate reductase 1 gene in families with cutis laxa type 2","volume":"85","author":"Guernsey","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1002\/ajmg.a.33747","article-title":"The phenotype caused by PYCR1 mutations corresponds to geroderma osteodysplasticum rather than autosomal recessive cutis laxa type 2","volume":"155","author":"Yildirim","year":"2011","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_14","first-page":"993","article-title":"A case of hereditary cutis laxa type IIB caused by PYCR1 gene mutation and literature review","volume":"44","author":"Xu","year":"2022","journal-title":"Zhejiang Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.ymgme.2013.08.009","article-title":"Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa","volume":"110","author":"Dimopoulou","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_16","first-page":"1391","article-title":"Congenital cutis laxa type 2 associated with recurrent aspiration pneumonia and growth delay: Case report","volume":"7","author":"Rahmati","year":"2015","journal-title":"Electron. Physician"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s00438-024-02173-y","article-title":"Confirming the enzymatic activity and neurodevelopmental trajectory of PYCR1 mutation in one child with autosomal-recessive cutis laxa type 2","volume":"299","author":"Shangguan","year":"2024","journal-title":"Mol. Genet. Genom."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Liang, S.T., Audira, G., Juniardi, S., Chen, J.-R., Lai, Y.-H., Du, Z.-C., Lin, D.-S., and Hsiao, C.-D. (2019). Zebrafish carrying pycr1 gene deficiency display aging and multiple behavioral abnormalities. Cells, 8.","DOI":"10.3390\/cells8050453"},{"key":"ref_19","unstructured":"National Library of Medicine (2026, January 22). PYCR1 Gene. MedlinePlus Genetics, Available online: https:\/\/medlineplus.gov\/genetics\/gene\/pycr1\/."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1007\/s10545-011-9319-3","article-title":"Defect in proline synthesis: Pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities","volume":"34","author":"Kretz","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2008S","DOI":"10.1093\/jn\/138.10.2008S","article-title":"The metabolism of proline as microenvironmental stress substrate","volume":"138","author":"Phang","year":"2008","journal-title":"J. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1007\/s00726-021-03051-2","article-title":"Proline metabolism and redox; maintaining a balance in health and disease","volume":"53","author":"Vettore","year":"2021","journal-title":"Amino Acids"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1002\/humu.23626","article-title":"Recommendations for interpreting the loss of function PVS1 ACMG\/AMP variant criterion","volume":"39","author":"Pesaran","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.ajhg.2023.06.002","article-title":"Using the ACMG\/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup","volume":"110","author":"Walker","year":"2023","journal-title":"Am. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13073-019-0690-2","article-title":"Recommendations for application of the functional evidence PS3\/BS3 criterion using the ACMG\/AMP sequence variant interpretation framework","volume":"12","author":"Brnich","year":"2019","journal-title":"Genome Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/s41586-019-1338-5","article-title":"Gene expression across mammalian organ development","volume":"571","author":"Halbert","year":"2019","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/s41586-019-1654-9","article-title":"Organoid single-cell genomic atlas uncovers human-specific features of brain development","volume":"574","author":"Kanton","year":"2019","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5688","DOI":"10.1038\/s41467-022-33364-z","article-title":"Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes","volume":"13","author":"Wang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Walters, K.F., Shukla, R., Kumar, V., Schueren, S., Yadav, H., Schilaty, N.D., and Jain, S. (2025). Resting-state EEG power spectral density analysis between healthy and cognitively impaired subjects. Brain Sci., 15.","DOI":"10.3390\/brainsci15020173"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1129\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T14:07:29Z","timestamp":1789567649000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/9\/1129"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,16]]},"references-count":30,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["genes17091129"],"URL":"https:\/\/doi.org\/10.3390\/genes17091129","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,16]]}}}