HER2 deficiency causes a developmental disorder with growth retardation and craniofacial malformations
Huaxiang Zhao, Pan Wang, Yuhua Jiao, Huimei Huang, Min Yu, Qing He, Chengkai Pan, Shuang Guo, Wenbin Huang, Yunfei Jia, Qianying Kong, Huifang Peng, Yandong Han, Yuxia Hou, Zhanping Ren, Yongwei Tao, Fei Huang, Hongwei Jiang, Shan Sun, Yanying Dong, Jiuxiang Lin, Chunyan Yin, Xuechen Zhu, Feng Chen, Yi Ding
Huaxiang Zhao, Pan Wang, Yuhua Jiao, Huimei Huang, Min Yu, Qing He, Chengkai Pan, Shuang Guo, Wenbin Huang, Yunfei Jia, Qianying Kong, Huifang Peng, Yandong Han, Yuxia Hou, Zhanping Ren, Yongwei Tao, Fei Huang, Hongwei Jiang, Shan Sun, Yanying Dong, Jiuxiang Lin, Chunyan Yin, Xuechen Zhu, Feng Chen, Yi Ding
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Research Article Development Genetics

HER2 deficiency causes a developmental disorder with growth retardation and craniofacial malformations

Abstract

The human epidermal growth factor receptor 2 (HER2) is a major therapeutic target in cancer. While the oncogenic effects of HER2 hyperactivation are well characterized, the biological consequences of its deficiency remain poorly defined. Here, through exome sequencing analyses of a cohort of 720 families affected by isolated or syndromic orofacial clefts, we unexpectedly identified 5 distinct rare germline HER2 variants in 5 unrelated families with growth deficits, orofacial clefts, and other craniofacial, skeletal, and auditory anomalies. In Xenopus embryos, these variants failed to recapitulate the developmental effects of WT HER2. In cultured cells, they disrupted HER2 protein stability, membrane localization, or site-specific phosphorylation, resulting in diminished ERK signaling. Strikingly, knock-in mice expressing a patient-derived HER2 variant and mice maternally exposed to Tucatinib, a recently approved anti-HER2 drug, both replicated patient phenotypes: delayed growth and diverse craniofacial abnormalities, including ocular dysgenesis, short jaws, and cleft palate. Collectively, our findings define a developmental disorder that we designate GRACE syndrome (Growth Retardation and Craniofacial Malformations Caused by HER2 Deficiency), establish HER2’s essential role in human growth and craniofacial morphogenesis, and reveal that HER2-targeted therapies during pregnancy can induce craniofacial defects and lifelong growth impairment in fetuses.

Authors

Huaxiang Zhao, Pan Wang, Yuhua Jiao, Huimei Huang, Min Yu, Qing He, Chengkai Pan, Shuang Guo, Wenbin Huang, Yunfei Jia, Qianying Kong, Huifang Peng, Yandong Han, Yuxia Hou, Zhanping Ren, Yongwei Tao, Fei Huang, Hongwei Jiang, Shan Sun, Yanying Dong, Jiuxiang Lin, Chunyan Yin, Xuechen Zhu, Feng Chen, Yi Ding

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Figure 1

Heterozygous missense HER2 variants cause growth impairment and craniofacial malformations.

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Heterozygous missense HER2 variants cause growth impairment and craniofa...
(A) Pedigrees of 5 families. Heterozygous HER2 variants and genotypes of available family members are indicated. Squares denote male family members, circles female family members, open symbols unaffected, and black symbols affected. mut, mutant. (B) Images of affected family members. Arrowheads mark cleft lip (top row), and arrows denote cleft palate (bottom row). For patient F3-II:2, lip and palate images were obtained at the ages of 1 year and 5 years, respectively. (C) Genomic and protein locations of HER2 variants (left) and the topological feature of HER2 in the plasma membrane (right). Variants are represented with stars. HER2 is comprised of an extracellular domain (ECD) with 4 subdomains (I, II, III, and IV), a single transmembrane domain (TM), and a cytoplasmic tyrosine kinase domain (TKD) followed by a C-terminal tail. (D) Protein sequence alignment of HER2 across various vertebrate species reveals the conservation of amino acids affected by the variants. Ser1150 is less conserved, while all other residues are highly conserved. (E) Structural modeling of the p.A87T variant. Ala87 is located on the C-terminal side of the parallel β-sheet in the extracellular domain I. It is buried within a hydrophobic cavity formed by Leu33, Leu85, Leu117, Thr63, and His88. Substituting alanine with threonine introduces a larger side chain containing a polar hydroxyl group, which may cause steric clashes (indicated by red disks) and disrupt the local hydrophobic environment. (F) Structural modeling of the p.R970W variant. Arg970 is positioned on the N-terminal side of Helix-I in the tyrosine kinase domain. Its positively charged side chain forms a salt bridge with Asp838 (indicated by yellow dashed lines). Substitution with tryptophan, which lacks a charged side chain, is predicted to disrupt this electrostatic interaction, potentially destabilizing the kinase domain.