Short Stature, Accelerated Bone Maturation, and Early Growth Cessation Due to Heterozygous Aggrecan Mutations
Short Stature, Accelerated Bone Maturation, and Early Growth Cessation Due to Heterozygous Aggrecan Mutations
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DOI：
10.1210/jc.2014-1332
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发表时间：
2014-08-01
影响因子：
5.8
通讯作者：
Dauber, Andrew
中科院分区：
文献类型：
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作者：
Nilsson, Ola;Guo, Michael H.;Dauber, Andrew
背景：许多特发性矮小儿童骨龄延迟。特发性身材矮小伴骨龄提前远不常见。目的：目的是确定潜在的遗传原因身材矮小伴骨龄提前。设置和设计：我们使用全外显子组测序研究三个常染色体显性身材矮小，骨龄提前，过早生长停止的家庭。结果：受影响的个体表现为身材矮小[成人身高-2.3至-4.2标准差评分（SDS）]，有早期生长停止或儿童期身材矮小病史（身高SDS -1.9至-3.5 SDS）、骨龄提前和正常内分泌评价。全外显子组测序鉴定了ACAN的新杂合变体，ACAN编码聚集蛋白聚糖，生长板和其他软骨组织细胞外基质中的蛋白聚糖。这些变异存在于所有受影响的家庭成员中，但没有未受影响的家庭成员。在家族1中，在外显子3（c.272delA）中鉴定了一种新的移码突变，预测其导致聚集蛋白聚糖蛋白的早期截短。在家族2中，在剪接供体位点内的高度保守位置发现碱基对取代（c. 2026 + 1G>A），这也可能改变大部分蛋白质的氨基酸序列。在家庭3中，错义变异（c.7064T>C）在外显子14影响一个高度保守的残基（L2355 P），并强烈预测扰乱蛋白质function.Conclusions：我们的研究表明，杂合子突变ACAN可导致轻度骨骼发育不良，临床表现为身材矮小，骨龄提前。骨骼成熟的加速效应以前没有注意到在人类ACAN突变的少数报告。因此，我们的研究结果扩大了ACAN缺陷的范围，并为出现身材矮小和骨骼加速成熟的不寻常儿童提供了新的分子遗传病因学。
Context: Many children with idiopathic short stature have a delayed bone age. Idiopathic short stature with advanced bone age is far less common.Objective: The aim was to identify underlying genetic causes of short stature with advanced bone age.Setting and Design: We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation.Results: Affected individuals presented with short stature [adult heights -2.3 to -4.2 standard deviation scores (SDS)] with histories of early growth cessation or childhood short stature (height SDS -1.9 to -3.5 SDS), advancement of bone age, and normal endocrine evaluations. Whole-exome sequencing identified novel heterozygous variants in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The variants were present in all affected, but in no unaffected, family members. In Family 1, a novel frameshift mutation in exon 3 (c.272delA) was identified, which is predicted to cause early truncation of the aggrecan protein. In Family 2, a base-pair substitution was found in a highly conserved location within a splice donor site (c. 2026 + 1G>A), which is also likely to alter the amino acid sequence of a large portion of the protein. In Family 3, a missense variant (c.7064T>C) in exon 14 affects a highly conserved residue (L2355P) and is strongly predicted to perturb protein function.Conclusions: Our study demonstrates that heterozygous mutations in ACAN can cause a mild skeletal dysplasia, which presents clinically as short stature with advanced bone age. The accelerating effect on skeletal maturation has not previously been noted in the few prior reports of human ACAN mutations. Our findings thus expand the spectrum of ACAN defects and provide a new molecular genetic etiology for the unusual child who presents with short stature and accelerated skeletal maturation.