Pathogenic Deep Intronic PCSK1 Variant Causes Proprotein Convertase 1/3 Deficiency in a Family.

IF 2.9 3区 医学 Q2 GENETICS & HEREDITY
Leah M Huber, Aslı Subaşıoğlu, Dorota Garczarczyk-Asim, Taras Valovka, Thomas Müller, Rüdiger Adam, Andreas R Janecke
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引用次数: 0

Abstract

Proprotein convertase 1/3 (PC1/3), encoded by PCSK1, is expressed in neuronal and endocrine cell types, where it activates a number of protein precursors that play roles in energy homeostasis. Biallelic PCSK1 loss-of-function mutations cause a polyendocrinopathy; a total of 34 patients were reported. An infant with congenital malabsorptive diarrhea of all carbohydrates underwent exome sequencing (ES), with particular consideration of PC1/3 deficiency, but no mutations were found. The onset of obesity in the second year of life increased suspicion of PC1/3 deficiency in the proband, as well as in his equally affected cousin. Transcript analysis revealed minor amounts of an aberrant PCSK1 transcript containing intron 9 sequence and encoding a premature stop codon (p.Pro400Valfs*35). A deep intronic PCSK1 variant, NG_021161.1(NM_000439.5):c.1196+2681T>A, was found to segregate in the proband's family with the disease. A minigene approach demonstrated that the identified deep-intronic variant underlies pseudo-exon inclusion of the intron 9 sequence in the transcript. The characteristic phenotype of PC1/3 deficiency might require extended genetic testing to make a timely diagnosis.

致病性深内含子PCSK1变异导致一个家族蛋白转化酶1/3缺失。
由PCSK1编码的蛋白转化酶1/3 (PC1/3)在神经细胞和内分泌细胞中表达,在这些细胞中,它激活一些在能量稳态中起作用的蛋白前体。双等位基因PCSK1功能缺失突变导致多内分泌病;共报告34例患者。一名患有先天性所有碳水化合物吸收不良腹泻的婴儿进行了外显子组测序(ES),特别考虑了PC1/3缺陷,但未发现突变。在出生后第二年开始的肥胖增加了先证者以及同样受影响的表亲对PC1/3缺乏的怀疑。转录本分析显示,少量的异常PCSK1转录本含有内含子9序列并编码一个过早停止密码子(p.Pro400Valfs*35)。深内含子PCSK1变异NG_021161.1(NM_000439.5):c。1196+ 2681t> A,在先证者家族中分离。minigene方法表明,鉴定的深内含子变异是转录本中内含子9序列的伪外显子包含的基础。PC1/3缺乏症的特征性表型可能需要进一步的基因检测才能及时诊断。
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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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