Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors

Abstract

Restrictive dermopathy (RD) is characterized by intrauterine growth retardation, tight and rigid skin with prominent superficial vessels, bone mineralization defects, dysplastic clavicles, arthrogryposis and early neonatal death. In two patients affected with RD, we recently reported two different heterozygous splicing mutations in the LMNA gene, leading to the production and accumulation of truncated Prelamin A. In other patients, a single nucleotide insertion was identified in ZMPSTE24. This variation is located in a homopolymeric repeat of thymines and introduces a premature termination codon. ZMPSTE24 encodes an endoprotease essential for the post-translational cleavage of the Lamin A precursor and the production of mature Lamin A. However, the autosomal recessive inheritance of RD suggested that a further molecular defect was present either in the second ZMPSTE24 allele or in another gene involved in Lamin A processing. Here, we report new findings in RD linked to ZMPSTE24 mutations. Ten RD patients were analyzed including seven from a previous series and three novel patients. All were found to be either homozygous or compound heterozygous for ZMPSTE24 mutations. We report three novel 'null' mutations as well as the recurrent thymine insertion. In all cases, we find a complete absence of both ZMPSTE24 and mature Lamin A associated with Prelamin A accumulation. Thus, RD is either a primary or a secondary laminopathy, caused by dominant de novo LMNA mutations or, more frequently, recessive null ZMPSTE24 mutations, most of which lie in a mutation hotspot within exon 9. The accumulation of truncated or normal length Prelamin A is, therefore, a shared pathophysiological feature in recessive and dominant RD. These findings have an important impact on our knowledge of the pathophysiology in Progeria and related disorders and will help direct the development of therapeutic approaches.

Truncated prelamin A expression in HGPS-like patients: a transcriptional study

“…11,[14][15][16]21,22 Using specific macros on ImageJ, we then analyzed the ratio of abnormal nuclei, based on DAPI staining in at least 100 cells, for patients 1 and 2, an HGPS patient and a healthy control. No differences were observed between patients' cells regarding the circularity (0.83 for HGPS, 0.78 for P1 and 0.80 for P2) but all patients presented a significantly higher level of circular nuclei in contrast to control cells (0.69% for control).…”

Mouse models of the laminopathies

“…Recessive mutations resulting in complete absence of ZMPSTE24 cause restrictive dermopathy, which is characterized by intrauterine growth retardation, rigid or tight skin with prominent superficial vessels, defects in bone mineralization, dysplastic clavicles, and early postnatal death [72,73]. Hypomorphic ZMPSTE24 alleles can lead to the accumulation of some unprocessed prelamin A in addition to mature lamin A, indicating residual activity of the mutated ZMPSTE24 protein.…”

“…Intriguingly, mice with complete loss of Zmpste24 do not develop the severe disease in human patients with restrictive dermopathy that is associated with perinatal death [73]. A study of Zmpste24 −/− mice revealed that ZMPSTE24 is absolutely required for the processing of farnesyl-prelamin A to mature lamin A [68,69].…”

New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update

“…1,2 In the original study, we were able to identify that this early lethal disorder is caused by lamin A-specific defects either due to dominant LMNA mutations or, in most cases, to recessive ZMPSTE24 null mutations. 1,3 Lamins are ubiquitous nuclear proteins constituting the type V intermediate filaments subfamily; they are subdivided in A-and B-type lamins, respectively encoded by the LMNA, LMNB1 or LMNB2 genes (OMIM reference #: 150330, 150340, 150341). 4,5 Lamins are major components of the nuclear lamina, a filamentous meshwork underlying the inner nuclear membrane involved in nuclear shape, nuclear pore complex spacing and resistance to mechanical stress.…”