Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorder of sex development by impeding Hedgehog protein palmitoylation and signaling.
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DOI：
10.1371/journal.pgen.1004340
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发表时间：
2014-05
期刊：
影响因子：
4.5
通讯作者：
Nef S
中科院分区：
文献类型：
--
作者：
Callier P;Calvel P;Matevossian A;Makrythanasis P;Bernard P;Kurosaka H;Vannier A;Thauvin-Robinet C;Borel C;Mazaud-Guittot S;Rolland A;Desdoits-Lethimonier C;Guipponi M;Zimmermann C;Stévant I;Kuhne F;Conne B;Santoni F;Lambert S;Huet F;Mugneret F;Jaruzelska J;Faivre L;Wilhelm D;Jégou B;Trainor PA;Resh MD;Antonarakis SE;Nef S
Hedgehog （Hh）家族的分泌蛋白在多种器官系统中作为形态因子控制胚胎模式和发育。翻译后胆固醇和棕榈酸酯在Hh蛋白上的共价附着对于多聚和远距离信号传导能力至关重要。然而，脂质修饰对Hh配体分布和人类信号接收的生物学影响尚不清楚。在本研究中，我们报告了一例独特的常染色体隐性综合征46，XY性发育障碍（DSD）伴睾丸发育不良和软骨发育不良，由刺猬酰基转移酶（HHAT）基因纯合G287V错义突变引起。这种突变发生在保守的膜结合o -酰基转移酶（MBOAT）结构域，并在实验中破坏了HHAT对棕榈酰化Hh蛋白（如DHH和SHH）的能力。与患者表型一致的是，在性别决定时，HHAT在XX和XY性腺的体细胞中都有表达，小鼠的HHAT功能丧失再现了在人类中观察到的大多数睾丸、骨骼、神经元和生长缺陷。在发育中的睾丸中，HHAT不是支持细胞承诺所必需的，但在睾丸索的形成和胎儿间质细胞的分化中起作用。总之，这些结果揭示了Hh蛋白的作用机制。此外，他们提供了Hh蛋白脂质修饰在人类睾丸器官发生和胚胎发育中发挥重要作用的第一个临床证据。性腺发育障碍代表了由性腺发育缺陷和/或睾丸/卵巢分化失败引起的临床和遗传异质性的DSD。不幸的是，在许多情况下，DSD的遗传病因是未知的，这表明我们对介导性别决定的因素的了解是有限的。对1例常染色体隐性综合征46，XY DSD合并睾丸发育不良和软骨发育不良患者进行外显子组测序，在o -乙酰基转移酶HHAT基因编码序列中发现了一个纯合错义突变（G287V）。HHAT基因编码一种粘接棕榈酰残基所需的酶，而棕榈酰残基对于hedgehog分泌蛋白的多聚和远距离信号传导能力至关重要。我们发现HHAT在胎儿发育期间广泛表达于人体器官，包括睾丸和卵巢，大约在性别决定时期。体外实验表明，G287V突变损害HHAT棕榈酰转移酶活性，缺乏功能性HHAT的小鼠表现出睾丸发育不良以及其他骨骼、神经元和生长缺陷，这些缺陷概括了综合征46，xy DSD患者的大多数方面。这些数据首次提供了刺猬蛋白脂质修饰在人类睾丸器官发生和胚胎发育中发挥重要作用的临床证据。
The Hedgehog (Hh) family of secreted proteins act as morphogens to control embryonic patterning and development in a variety of organ systems. Post-translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency. However, the biological impact of lipid modifications on Hh ligand distribution and signal reception in humans remains unclear. In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene. This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH. Consistent with the patient phenotype, HHAT was found to be expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans. In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells. Altogether, these results shed new light on the mechanisms of action of Hh proteins. Furthermore, they provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development. Disorders of gonadal development represent a clinically and genetically heterogeneous class of DSD caused by defects in gonadal development and/or a failure of testis/ovarian differentiation. Unfortunately, in many cases the genetic aetiology of DSD is unknown, indicating that our knowledge of the factors mediating sex determination is limited. Using exome sequencing on a case of autosomal recessive syndromic 46,XY DSD with testicular dysgenesis and chondrodysplasia, we found a homozygous missense mutation (G287V) within the coding sequence of the O-acetyl-transferase HHAT gene. The HHAT gene encodes an enzyme required for the attachment of palmitoyl residues that are critical for multimerization and long range signaling potency of hedgehog secreted proteins. We found that HHAT is widely expressed in human organs during fetal development, including testes and ovaries around the time of sex determination. In vitro assays show that G287V mutation impairs HHAT palmitoyl-transferase activity and mice lacking functional Hhat exhibit testicular dysgenesis as well as other skeletal, neuronal and growth defects that recapitulate most aspects of the syndromic 46,XY DSD patient. These data provide the first clinical evidence of the essential role played by lipid modification of Hedgehog proteins in human testicular organogenesis and embryonic development.
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影响因子：
3.6
作者：
Clark, AM;Garland, KK;Russell, LD
通讯作者：
Russell, LD
影响因子：
4
作者：
Canto, P;Vilchis, F;Méndez, JP
通讯作者：
Méndez, JP
影响因子：
2.7
作者：
Lee, JD;Kraus, P;Treisman, JE
通讯作者：
Treisman, JE
DOI：
10.1073/pnas.87.3.1052
发表时间：
1990-02-01
影响因子：
11.1
作者：
EGAN, JJ;SALTIS, J;LONDOS, C
通讯作者：
LONDOS, C
影响因子：
4.8
作者：
Buglino, John A.;Resh, Marilyn D.
通讯作者：
Resh, Marilyn D.