A homozygousZMPSTE24null mutation in combination with a heterozygous mutation in theLMNAgene causes Hutchinson-Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS

Abstract

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 ZMPSTE24 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.

Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation

“…14 The second patient carried a homozygous ZMPSTE24 frameshift deletion associated with an LMNA heterozygous nonsense mutation that 'rescued' the patient's phenotype, most probably by reducing to half the amounts of accumulated prelamin A, as in the double-knockout Zmpste24 À/À Lmna +/À mice. 15,31 This patient showed features compatible with a severe form of MADB, but was described as being affected with HGPS. 15 In this last report, the authors concluded that the LMNA truncation is a salvage alteration modifying the clinical picture from RD to HGPS by preventing farnesylation of the accumulated prelamin A or by reducing the amount of accumulated prelamin A.…”

“…15,31 This patient showed features compatible with a severe form of MADB, but was described as being affected with HGPS. 15 In this last report, the authors concluded that the LMNA truncation is a salvage alteration modifying the clinical picture from RD to HGPS by preventing farnesylation of the accumulated prelamin A or by reducing the amount of accumulated prelamin A. This second hypothesis is more probable from our point of view, as no truncated lamin A isoform was visible on the western blot.…”

“…10,11,[14][15][16] Whereas the ZMPSTE24 mutations found in MADB encoded a protein with considerably reduced residual activity, the mutations found in RD led to null ZMPSTE24 activity, strongly suggesting a positive correlation between residual enzyme activity, accumulated prelamin A levels and the severity of the phenotype. 17 In Zmpste24-knockout mice, severe growth retardation, skeletal abnormalities, including small mandible, lipodystrophy, cardiomyopathy and muscular dystrophy, were reported, as well as premature death, with these features being associated with a complete absence of mature lamin A and an exclusive production of prelamin A.…”

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

“…The patient carried a homozygous ZMPSTE24 frame-shift mutation (p.Val402Serfs*2) associated with a LMNA nonsense mutation (p.Arg654*) acting as a salvage alteration alleviating the clinical picture from RD to HGPS-like. 26 Thill et al 17 presented an exception to the rule. They described a typical RD phenotype in a patient carrying only a heterozygous missense mutation (p.Leu462Arg).…”

“…Other mutations were found in additional cases of RD [15][16][17][18][19][20][21] and progeroid syndromes phenotypically overlapping with MAD and HGPS that can be nosologically classified as MAD-B, given the common molecular basis, involving ZMPSTE24 deficiency. 13,[22][23][24][25][26][27][28] RD, MAD-B and HGPS share a common pathophysiological mechanism based on the abnormal accumulation of a wild type or modified lamin A precursors.…”