A homozygous telomerase T-motif variant resulting in markedly reduced repeat addition processivity in siblings with Hoyeraal Hreidarsson syndrome
A homozygous telomerase T-motif variant resulting in markedly reduced repeat addition processivity in siblings with Hoyeraal Hreidarsson syndrome
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DOI：
10.1182/blood-2012-08-447755
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发表时间：
2013-05-02
期刊：
影响因子：
20.3
通讯作者：
Bertuch, Alison A.
中科院分区：
文献类型：
--
作者：
Gramatges, Maria M.;Qi, Xiaodong;Bertuch, Alison A.
Hoyeraal Hreidarsson综合征（HHS）是一种先天性角化不良（DC），其特征为骨髓衰竭、宫内生长迟缓、发育迟缓、小头畸形、小脑发育不全、免疫缺陷和极短的端粒。与DC一样，在HHS患者中发现了编码端粒维持所需因子（如端粒酶逆转录酶（TERT））的基因突变。我们描述了2个兄弟姐妹HHS的情况下所造成的homozygousmutation（p.T567M）内的端粒酶T基序。这种突变导致端粒酶合成端粒重复序列的能力显著降低，表明T基序在端粒酶功能的这一独特方面发挥作用。我们通过证明先前报道的p.K570N T基序突变中的持续合成能力缺陷来支持这一发现。近亲，杂合子p.T567M父母表现出端粒长度约第一百分位数，没有证据表明DC表型。尽管杂合子持续合成能力缺陷与家族性、成人型肺纤维化相关，但这些病例表明双等位基因持续合成能力突变对临床和功能有严重影响。因此，尽管保留的能力，添加短的端粒重复序列的最短的端粒，单独表达的端粒酶持续合成突变体可能会导致一个深刻的失败的端粒维护和早发性多系统疾病。
Hoyeraal Hreidarsson syndrome (HHS) is a form of dyskeratosis congenita (DC) characterized by bone marrow failure, intrauterine growth retardation, developmental delay, microcephaly, cerebellar hypoplasia, immunodeficiency, and extremely short telomeres. As with DC, mutations in genes encoding factors required for telomere maintenance, such as telomerase reverse transcriptase (TERT), have been found in patients with HHS. We describe 2 sibling HHS cases caused by a homozygousmutation (p.T567M) within the TERT T motif. This mutation resulted in a marked reduction in the capacity of telomerase to processively synthesize telomeric repeats, indicating a role for the T motif in this unique aspect of telomerase function. We support this finding by demonstrating defective processivity in the previously reported p.K570N T-motif mutation. The consanguineous, heterozygous p.T567M parents exhibited telomere lengths around the first percentile and no evidence of a DC phenotype. Although heterozygous processivity defects have been associated with familial, adult-onset pulmonary fibrosis, these cases demonstrate the severe clinical and functional impact of biallelic processivity mutations. Thus, despite retaining the capacity to add short stretches of telomeric repeats onto the shortest telomeres, sole expression of telomerase processivity mutants can lead to a profound failure of telomere maintenance and early-onset multisystem disease.