A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation 4 in the LMNA gene causes Hutchinson-Gilford progerlia syndrome (HGPS): Insights into the pathophysiology of HGPS

作者：Denecke Jonas^*; Brune Thomas; Feldhaus Tobias; Robenek Horst; Robenek Horst; Kranz Christian; Auchus Richard J; Agarwal Anil K; Marquardt Thorsten

来源：Human Mutation, 2006, 27(6): 524-531.

DOI：10.1002/humu.20315

• Hutchinson-Gilford progeria syndrome
• HGPS
• lamin A
• LMNA
• ZMPSTE24
• mandibuloacral clysplasia
• aging disorder
• nuclear lamina

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder normally caused by a spontaneous heterozygous mutation in the LMNA gene that codes for the nuclear lamina protein lamin A. Several enzymes are involved in the processing of its precursor, prelamin A, to the mature lamin A. A functional knockout of one of the enzymes involved in prelamin A processing, the zinc metalloprotease ZMPSTE24, causes an even more severe disorder with early neonatal death described as restrictive dermatopathy (RD). This work describes a HGPS patient with a combined defect of a homozygous loss-of-function mutation in the ZMPSTE24 gene and a heterozygous mutation in the LMNA gene that results in a C-terminal elongation of the final lamin A. Whereas the loss of function mutation of ZNWSTE24 normally results in lethal RD, the truncation of LMNA seems to be a salvage alteration alleviating the clinical picture to the HGPS phenotype. The mutations of our patient indicate that farnesylated prelamin A is the deleterious agent leading to the HGPS phenotype, which gives further insights into the pathophysiology of the disorder.

• 出版日期2006-6