Center of Excellence in Medical Genetics Research, Chiang Mai University, Chiang Mai, Thailand.
Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand.
Clin Genet. 2019 Jan;95(1):132-139. doi: 10.1111/cge.13434. Epub 2018 Sep 10.
Split-hand/foot malformation (SHFM) is caused by mutations in TP63, DLX5, DLX6, FGF8, FGFR1, WNT10B, and BHLHA9. The clinical features of SHFM caused by mutations of these genes are not distinguishable. This implies that in normal situations these SHFM-associated genes share an underlying regulatory pathway that is involved in the development of the central parts of the hands and feet. The mutations in SHFM-related genes lead to dysregulation of Fgf8 in the central portion of the apical ectodermal ridge (AER) and subsequently lead to misexpression of a number of downstream target genes, failure of stratification of the AER, and thus SHFM. Syndactyly of the remaining digits is most likely the effects of dysregulation of Fgf-Bmp-Msx signaling on apoptotic cell death. Loss of digit identity in SHFM is hypothesized to be the effects of misexpression of HOX genes, abnormal SHH gradient, or the loss of balance between GLI3A and GLI3R. Disruption of canonical and non-canonical Wnt signaling is involved in the pathogenesis of SHFM. Whatever the causative genes of SHFM are, the mutations seem to lead to dysregulation of Fgf8 in AER cells of the central parts of the hands and feet and disruption of Wnt-Bmp-Fgf signaling pathways in AER.
并指（趾）畸形（SHFM）是由 TP63、DLX5、DLX6、FGF8、FGFR1、WNT10B 和 BHLHA9 基因突变引起的。这些基因的突变引起的 SHFM 的临床特征无法区分。这意味着在正常情况下，这些与 SHFM 相关的基因共享一个潜在的调节途径，该途径参与手和脚的中央部分的发育。SHFM 相关基因的突变导致中央顶外脊（AER）中 Fgf8 的失调，随后导致许多下游靶基因的表达错误、AER 分层失败，从而导致 SHFM。剩余手指的并指最有可能是 Fgf-Bmp-Msx 信号转导失调对细胞凋亡的影响。SHFM 中失去指（趾）的特征可能是 HOX 基因表达错误、异常 SHH 梯度或 GLI3A 和 GLI3R 之间失衡的结果。经典和非经典 Wnt 信号转导的破坏参与了 SHFM 的发病机制。无论 SHFM 的致病基因是什么，突变似乎都会导致手和脚中央部分 AER 细胞中 Fgf8 的失调，并破坏 AER 中的 Wnt-Bmp-Fgf 信号通路。
