Identification of a common PEX1 mutation in Zellweger syndrome

The Zellweger spectrum of disease, encompassing Zellweger syndrome and the progressively milder phenotypes of neonatal adrenoleukodystrophy and infant ile Refsum disease, is due to a failure to form functional peroxisomes. Cel l fusion complementation studies demonstrated that these diseases are genet ically heterogeneous, with two-thirds of all patients lying within a single complementation group, CG1, Molecular genetic and cell biology studies hav e shown that PEX1 is deficient in many CG1 patients. However, previous stud ies have focused on mildly affected patients and there is still no report o f two mutant PEX1 alleles in any Zellweger syndrome patient. Furthermore, m utations in the PMP70 gene have also been identified in two Zellweger syndr ome patients from CG1, raising the possibility that CG1 patients may repres ent a mixture of PEX1-deficient and PMP70 deficient individuals. To address the molecular basis of disease in Zellweger syndrome patients from CG1, we examined all 24 PEX1 exons in four patients, including both patients that have mutations in PMP70. PEX1 mutations were detected in all four patients, including a 1-bp insertion (c.2097insT) in exon 13 that was present in thr ee of the four patients. Subsequent studies demonstrated that this mutation is present in one-half of all CG1 patients and correlates with the Zellweg er syndrome phenotype. As this mutation leads to a loss of protein function its frequency makes it the most common cause of Zellweger syndrome, helpin g to explain the high percentage of patients that belong to CG1, Hum Mutat 14:45-53, 1999. (C) 1999 Wiley-Liss, Inc.