Identification and Functional Characterization of Two Intronic NIPBL Mutations in Two Patients with Cornelia de Lange Syndrome
نویسندگان
چکیده
Cornelia de Lange syndrome (CdLS) is a rare genetically heterogeneous disorder with a high phenotypic variability including mental retardation, developmental delay, and limb malformations. The genetic causes in about 30% of patients with CdLS are still unknown. We report on the functional characterization of two intronic NIPBL mutations in two patients with CdLS that do not affect a conserved splice-donor or acceptor site. Interestingly, mRNA analyses showed aberrantly spliced transcripts missing exon 28 or 37, suggesting the loss of the branch site by the c.5329-15A>G transition and a disruption of the polypyrimidine by the c.6344del(-13)_(-8) deletion. While the loss of exon 28 retains the reading frame of the NIBPL transcript resulting in a shortened protein, the loss of exon 37 shifts the reading frame with the consequence of a premature stop of translation. Subsequent quantitative PCR analysis demonstrated a 30% decrease of the total NIPBL mRNA levels associated with the frameshift transcript. Consistent with our results, this patient shows a more severe phenotype compared to the patient with the aberrant transcript that retains its reading frame. Thus, intronic variants identified by sequencing analysis in CdLS diagnostics should carefully be examined before excluding them as nonrelevant to disease.
منابع مشابه
سندرم Cornelia de Lange و معرفی یک مورد شیرخوار مبتلا
Cornelia De Lange is a rare congenital syndrome with multiple anomalies including Facial dysmorphism, hirsutism, height, weight and head circumflex retardations, cardiac defects, gastrointestinal and renal defects and extremity anomaly. Prevalence of this syndrome is 1 to 30000 or 1 to 50000. The diagnosis of this syndrome is based on clinical evidence. Genetic foundation is known to have two...
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ورودعنوان ژورنال:
دوره 2016 شماره
صفحات -
تاریخ انتشار 2016