A germline or de novo mutation in two families with Gaucher disease: implications for recessive disorders

Abstract

Gaucher disease (GD) is an autosomal recessive storage disorder that most commonly results from the inheritance of one identifiable mutant glucocerebrosidase (GBA1) allele from each parent. Here, we report two cases of type 2 GD resulting from the inheritance of one identifiable paternal mutant allele and one allele that likely resulted from a maternal germline mutation. Germline mutations or mosiacism are not generally associated with autosomal recessive disorders. The probands from the two unrelated families had the same maternal mutation, leu444pro, that we propose resulted from a de novo maternal germline mutation occurring at this known 'hotspot' for mutation. This first report of a germline mutation for a common point mutation leu444pro (c.1448 T>C;p.leu483pro) in GD has significant implications for molecular diagnostics and genetic counseling in recessive disorders.

Figure 1

Studies in Family no. 1. (a) Chromatograms showing GBA1 sequence including the proband, mother and father. Each individual genotype has been labeled. (b) Western blot probed with antibody to GCase performed on total protein extracted from the proband, mother and two WT controls fibroblast cell lines. GCase levels were compared with β-actin. (c) GCase activity measured in fibroblast extracts from the proband, mother and two WT controls.