Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of x-linked hypophosphatemic rickets that mimics an autosomal dominant trait
Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of x-linked hypophosphatemic rickets that mimics an autosomal dominant trait
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DOI：
10.1210/jc.2005-1776
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发表时间：
2006-02-01
影响因子：
5.8
通讯作者：
Matsuo, M
中科院分区：
文献类型：
--
作者：
Goji, K;Ozaki, K;Matsuo, M
内容：家族性低磷血症性佝偻病通常以X连锁显性遗传病（XLH）的形式传播，尽管也观察到常染色体显性形式。这些疾病的遗传学研究已经确定PHEX和FGF 23突变分别是X连锁显性遗传病和常染色体显性遗传形式的原因。目的：本研究的目的是描述一个患有低磷血症佝偻病的家族的分子遗传学发现，该家族具有假定的常染色体显性遗传。患者：我们研究了一个家庭，其中父亲和两个女儿的大女儿（但第二个女儿没有）患有低磷血症性佝偻病。家系的解释表明，遗传传播的疾病发生的常染色体显性trait.Methods和结果：直接核苷酸测序的FGF23和PHEX显示，大女儿是杂合子的R567X突变的PHEX，而不是FGF23，这表明遗传传播发生的X连锁显性性状。出乎意料的是，父亲是这种突变的杂合子。单核苷酸引物延伸和变性HPLC分析的父亲使用DNA从单毛根显示，他是一个体细胞嵌合体的突变。单倍型分析证实，父亲将X染色体上18个标记的基因型平均遗传给了他的两个女儿。事实上，父亲传递的突变，只有他的两个女儿之一，表明他是一个种系嵌合的mutation.Conclusions：体细胞和种系嵌合的X连锁显性突变PHEX可能模仿常染色体显性遗传。
Context: Familial hypophosphatemic rickets is usually transmitted as an X-linked dominant disorder (XLH), although autosomal dominant forms have also been observed. Genetic studies of these disorders have identified mutations in PHEX and FGF23 as the causes of X-linked dominant disorder and autosomal dominant forms, respectively.Objective: The objective of the study was to describe the molecular genetic findings in a family affected by hypophosphatemic rickets with presumed autosomal dominant inheritance.Patients: We studied a family in which the father and the elder of his two daughters, but not the second daughter, were affected by hypophosphatemic rickets. The pedigree interpretation of the family suggested that genetic transmission of the disorder occurred as an autosomal dominant trait.Methods and Results: Direct nucleotide sequencing of FGF23 and PHEX revealed that the elder daughter was heterozygous for an R567X mutation in PHEX, rather than FGF23, suggesting that the genetic transmission occurred as an X-linked dominant trait. Unexpectedly, the father was heterozygous for this mutation. Single-nucleotide primer extension and denaturing HPLC analysis of the father using DNA from single hair roots revealed that he was a somatic mosaic for the mutation. Haplotype analysis confirmed that the father transmitted the genotypes for 18 markers on the X chromosome equally to his two daughters. The fact that the father transmitted the mutation to only one of his two daughters indicated that he was a germline mosaic for the mutation.Conclusions: Somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance.