{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T17:14:12Z","timestamp":1779297252652,"version":"3.51.4"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T00:00:00Z","timestamp":1606435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Context<\/jats:title><jats:p>Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessively inherited disorder due to loss-of-function mutations in the <jats:italic>CYP27B1<\/jats:italic> gene. <jats:italic>CYP27B1<\/jats:italic> encodes an enzyme of 25-hydroxyvitamin D-1\u03b1-hydroxylase for converting inactive 25-OHD to biologically active 1,25-(OH)<jats:sub>2<\/jats:sub>D.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To identify underlying genetic defects in patients with VDDR1A.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twelve patients from 7 Turkish and 2 Saudi families were investigated. The coding exons and intron-exon boundaries of the <jats:italic>CYP27B1<\/jats:italic> gene were amplified by Polymerase Chain Reaction (PCR) from peripheral lymphocyte DNA. PCR products were directly sequenced. The consequences of c.590G &amp;gt; A mutation were analyzed by <jats:italic>in silico<\/jats:italic> and functional analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>CYP27B1<\/jats:italic> mutations were identified in all the patients. Two novel mutations were identified in two separate families: c.171delG (family 7) and c.398_400dupAAT (family 8). The intra-exon deletion of c.171delG resulted in a frameshift and premature stop codon 20 amino acids downstream from the mutation (p.L58Cfs<jats:sup>\u2217<\/jats:sup>20). The intra-exon duplication of c.398_400dupAAT generated a premature stop codon at the mutation site (p.W134<jats:sup>\u2217<\/jats:sup>). A missense c.590G &amp;gt; A (p.G197D) mutation was found in a patient from family 4 and caused a defect in pre-mRNA splicing. As a result, two populations of transcripts were detected: the majority of them with intron 3 retention (83%), and the minority (17%) being properly spliced transcripts with about 16% of wild-type enzymatic activity. The remaining nine patients from six families carried a previously reported c.1319_1325dupCCCACCC (F443Pfs<jats:sup>\u2217<\/jats:sup>24) mutation. Clinically, all the patients need continued calcitriol treatment, which was consistent with inactivation of 25-hydroxy vitamin D1\u03b1-hydroxylase activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Two novel frameshift <jats:italic>CYP27B1<\/jats:italic> mutations were identified and predicted to inactivate 25-hydroxyvitamin D-1\u03b1-hydroxylase. The loss of enzymatic activity by c.590G &amp;gt; A missense mutation was mainly caused by aberrant pre-mRNA splicing.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2020.607517","type":"journal-article","created":{"date-parts":[[2020,11,27]],"date-time":"2020-11-27T07:13:45Z","timestamp":1606461225000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Molecular Analysis of CYP27B1 Mutations in Vitamin D-Dependent Rickets Type 1A: c.590G &gt; A (p.G197D) Missense Mutation Causes a RNA Splicing Error"],"prefix":"10.3389","volume":"11","author":[{"given":"Minjing","family":"Zou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayla","family":"Guven","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huda A.","family":"BinEssa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roua A.","family":"Al-Rijjal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian F.","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali S.","family":"Alzahrani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yufei","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2020,11,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"88","DOI":"10.4274\/jcrpe.2017.s008","article-title":"Genetic Causes of Rickets.","volume":"9","author":"Acar","year":"2017","journal-title":"J. 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