Paternal GNAS Mutations Lead to Severe Intrauterine Growth Retardation (IUGR) and Provide Evidence for a Role of XLαs in Fetal Development
Paternal GNAS Mutations Lead to Severe Intrauterine Growth Retardation (IUGR) and Provide Evidence for a Role of XLαs in Fetal Development
复制标题
DOI：
10.1210/jc.2013-1667
复制
发表时间：
2013-09-01
影响因子：
5.8
通讯作者：
Kottler, Marie-Laure
中科院分区：
文献类型：
--
作者：
Richard, Nicolas;Molin, Arnaud;Kottler, Marie-Laure
内容：杂合GNAS失活突变导致假性甲状旁腺功能减退Ia型（PHP-Ia）时，母系遗传和假性甲状旁腺功能减退（PPHP）/进行性骨发育不全（POH）时，父系遗传。最近的研究表明，父亲，而不是母亲，GNAS等位基因的突变可能与胎儿宫内生长迟缓（IUGR），因此小尺寸的胎龄。目的：该研究的目的是确认和扩大这些发现在大量的患者提出无论是PHP-Ia或PPHP/POH。患者和方法：我们收集了PHP-Ia（n = 29）或PPHP/POH（n = 26）患者的出生参数（即胎龄、体重、身长和头围），这些患者经证实存在GNAS突变。携带突变的父母等位基因进行了评估，通过调查的父母，或当一个从头突变被确定，通过信息intragenic polymorphisms.Results：杂合GNAS突变的父母等位基因与IUGR。然而，当这些突变位于父亲GNAS等位基因上时，IUGR比母亲等位基因上的突变明显得多。此外，出生体重较低的父亲GNAS突变影响外显子2-13比外显子1/内含子1 mutations.Conclusions：这些数据表明，父亲衍生的GNAS转录，可能XL α s，是正常的胎儿生长和发育所需的，这种转录影响胎盘功能。因此，类似于其他印记基因，GNAS控制生长和/或胎儿发育。
Context: Heterozygous GNAS inactivating mutations cause pseudohypoparathyroidism type Ia (PHP-Ia) when maternally inherited and pseudopseudohypoparathyroidism (PPHP)/progressive osseous heteroplasia (POH) when paternally inherited. Recent studies have suggested that mutations on the paternal, but not the maternal, GNAS allele could be associated with intrauterine growth retardation (IUGR) and thus small size for gestational age.Objectives: The aim of the study was to confirm and expand these findings in a large number of patients presenting with either PHP-Ia or PPHP/POH.Patients and Methods: We collected birth parameters (ie, gestational age, weight, length, and head circumference) of patients with either PHP-Ia (n = 29) or PPHP/POH (n = 26) with verified GNAS mutations. The parental allele carrying the mutation was assessed by investigating the parents or, when a de novo mutation was identified, through informative intragenic polymorphisms.Results: Heterozygous GNAS mutations on either parental allele were associated with IUGR. However, when these mutations are located on the paternal GNAS allele, IUGR was considerably more pronounced than with mutations on the maternal allele. Moreover, birth weights were lower with paternal GNAS mutations affecting exons 2-13 than with exon 1/intron 1 mutations.Conclusions: These data indicate that a paternally derived GNAS transcript, possibly XL alpha s, is required for normal fetal growth and development and that this transcript affects placental functions. Thus, similar to other imprinted genes, GNAS controls growth and/or fetal development.