Details

Autor(en) / Beteiligte

• Lin, Wei-Xia
• Deng, Li-Jing
• Liu, Rui
• Qiu, Jian-Wu
• Cheng, Yin
• Zhang, Zhan-Hui
• Chen, Feng-Ping
• Song, Yuan-Zong

Titel

Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency: In vivo and in vitro studies of the aberrant transcription arising from two novel splice-site variants in SLC25A13

Ist Teil von

• European journal of medical genetics, 2021-03, Vol.64 (3), p.104145-104145, Article 104145

Ort / Verlag

Netherlands: Elsevier Masson SAS

Erscheinungsjahr

2021

Quelle

Access via ScienceDirect (Elsevier)

Beschreibungen/Notizen

• Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) is an autosomal recessive disease resulting from biallelic SLC25A13 mutations, and its diagnosis relies on genetic analysis. This study aimed to characterize the pathogenicity of 2 novel splice-site variants of SLC25A13 gene. Two patients (C0476 and C0556) suspected to have NICCD, their family members and 9 healthy volunteers were recruited as the research subjects. The SLC25A13 genotypes NG_012247.2(NM_014251.3): c.[852_855del]; [69+5G > A] in patient C0476 and c.[1453-1G > A]; [1751–5_1751-4ins (2684)] in patient C0556 were identified by means of polymerase chain reaction, long and accurate polymerase chain reaction, as well as Sanger sequencing. The 2 splice-site variants were absent in control databases and predicted to be pathogenic by computational analysis. The alternative splice variants in monocyte-derived macrophages from patient C0476 demonstrated exon 2 skipping [r.16_69del; p.(Val6_Lys23del)] in vivo, while minigene analysis revealed both exon 2-skipping and retained products from c.69+5G > A in vitro. In the patient C0556, an aberrant transcript [r.1453del; p.(Gly485Valfs*22)] resulting from c.1453-1G > A was detected on minigene splicing study. Thus, c.69+5G > A and c.1453-1G > A were both proved to be pathogenic. The 2 novel splice-site variants expanded the SLC25A13 mutation spectrum and provided reliable molecular markers for the definite diagnosis and genetic counseling of NICCD in the affected families. •Two novel SLC25A13 splice-site variants, c.69+5G>Aand c.1453-1G>A, were identified in NICCD patients and proved to be pathogenic.•Transcriptanalysisin M-Mϕsand minigene analysis were feasible to clarify the pathogenicity of splice-site variants.•There were ASVs structural differences between the M-Mϕs and PBMCs.