BRF1 mutations in a family with growth failure, markedly delayed bone age, and central nervous system anomalies
BRF1 mutations in a family with growth failure, markedly delayed bone age, and central nervous system anomalies
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DOI：
10.1111/cge.12887
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发表时间：
2017-05-01
影响因子：
3.5
通讯作者：
Baron, J.
中科院分区：
文献类型：
--
作者：
Jee, Y. H.;Sowada, N.;Baron, J.
线性生长障碍可以由许多不同的遗传异常引起。在许多情况下，遗传缺陷不仅影响生长板，导致身材矮小，还影响其他器官/组织，导致其他临床异常。对1例10岁男孩的出生后线性生长受损（身高113.3 cm，-4.6 SDS）、骨龄延迟5岁、畸形面容、认知障碍和中枢神经系统异常进行了评价。他的弟弟，在10个月大时只出现生长障碍。外显子组测序鉴定了两个受累同胞中编码RNA聚合酶III转录起始因子90 kDa亚基（BRF 1）的基因的复合杂合变体：错义突变（c.875 C>G：p.P292R）和移码突变（c.551delG：p.C184Sfs）。移码突变预期导致无义介导的mRNA衰减（NMD）和/或蛋白质截短。具有P292 R错义突变的BRF 1的表达未能拯救缺乏BRF 1的酵母。这些发现证实了之前的一份报告，即BRF 1的双等位基因突变导致小脑-面部-牙齿综合征。我们的研究结果也有助于定义生长表型，表明线性生长障碍在神经系统异常之前可以在临床上变得明显，并且骨龄严重延迟可以作为诊断线索。
Linear growth failure can be caused by many different genetic abnormalities. In many cases, the genetic defect affects not only the growth plate, causing short stature but also other organs/tissues causing additional clinical abnormalities. A 10-year old boy was evaluated for impaired postnatal linear growth (height 113.3cm, -4.6 SDS), a bone age that was delayed by 5 years, dysmorphic facies, cognitive impairment, and central nervous system anomalies. His younger brother, presented only with growth failure at 10 months of age. Exome sequencing identified compound heterozygous variants in the gene encoding RNA polymerase III transcription initiation factor 90 kDa subunit (BRF1) in both affected siblings: a missense mutation (c.875 C>G:p.P292R) and a frameshift mutation (c.551delG:p.C184Sfs). The frameshift mutation is expected to lead to nonsense-mediated mRNA decay (NMD) and/or to protein truncation. Expression of BRF1 with the P292R missense mutation failed to rescue yeast lacking BRF1. The findings confirm a previous report showing that biallelic mutations in BRF1 cause cerebellar-facial-dental syndrome. Our findings also help define the growth phenotype, indicating that the linear growth failure can become clinically evident before the neurological abnormalities and that a severely delayed bone age may serve as a diagnostic clue.