Pmp22 super-enhancer deletion causes tomacula formation and conduction block in peripheral nerves

Abstract

Copy number variation of the peripheral nerve myelin gene Peripheral Myelin Protein 22 (PMP22) causes multiple forms of inherited peripheral neuropathy. The duplication of a 1.4 Mb segment surrounding this gene in chromosome 17p12 (c17p12) causes the most common form of Charcot-Marie-Tooth disease type 1A, whereas the reciprocal deletion of this gene causes a separate neuropathy termed hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is robustly induced in Schwann cells in early postnatal development, and several transcription factors and their cognate regulatory elements have been implicated in coordinating the gene’s proper expression. We previously found that a distal super-enhancer domain was important for Pmp22 expression in vitro, with particular impact on a Schwann cell-specific alternative promoter. Here, we investigate the consequences of deleting this super-enhancer in vivo. We find that loss of the super-enhancer in mice reduces Pmp22 expression throughout development and into adulthood, with greater impact on the Schwann cell-specific promoter. Additionally, these mice display tomacula formed by excessive myelin folding, a pathological hallmark of HNPP, as have been previously observed in heterozygous Pmp22 mice as well as sural biopsies from patients with HNPP. Our findings demonstrate a mechanism by which smaller copy number variations, not including the Pmp22 gene, are sufficient to reduce gene expression and phenocopy a peripheral neuropathy caused by the HNPP-associated deletion encompassing PMP22.

Three‐dimensional genome structure and function

“…Such changes can cause the dysregulation of gene expression, contributing to various human diseases and developmental disorders (Figure 4A). [267][268][269][270][271][272] Sox9 is located within a 2 Mb TAD, 273,274 containing multiple tissue-specific enhancers that participate in mammalian sex determination, craniomaxillofacial development, and chondrogenesis. 268,[275][276][277] Located 1.45 and 1.25 Mb upstream of the Sox9 gene, remote enhancer clusters Ec1.45 and Ec1.25 regulate its tissue-specific expression in the mandibular process and the first branchial arch region.…”

Genome-Edited Coincidence and PMP22-HiBiT Fusion Reporter Cell Lines Enable an Artifact-Suppressive Quantitative High-Throughput Screening Strategy for PMP22 Gene-Dosage Disorder Drug Discovery

“…For example, the identification of lead compounds that increase Pmp22 could be candidates for treatment of the PMP22 haploinsufficiency in HNPP. We have recently shown that symptoms of HNPP are dependent upon the degree of reduction of Pmp22 levels in mouse models . Alternatively, similar screens could be implemented for known modifier genes of CMT1A and other disorders .…”

“…We have recently shown that symptoms of HNPP are dependent upon the degree of reduction of Pmp22 levels in mouse models. 52 Alternatively, similar screens could be implemented for known modifier genes of CMT1A and other disorders. 53 Overall, we have developed a series of in vitro assays and present a screening platform that can be used to identify novel chemical entities that could be exploited for the treatment of CMT1A.…”

Mechanisms and Treatments in Demyelinating CMT

“…In addition, a late myelinating Schwann cell enhancer (LMSE) has been identified upstream of the P1 promoter. LMSE is important in the later stages of myelination, as well as in remyelination following injury [66,67], and Pantera et al have shown that deleting the LMSE significantly reduces the expression of PMP-22 by disproportionately impacting the P1 promoter [68,69]. Small duplications containing LMSE can also result in mild forms of CMT1A, suggesting that the additional copy of the super-enhancer region can be disease causing independently of PMP-22 [55].…”