HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome

• Published in: Journal of medical genetics Vol. 52; no. 12; pp. 797 - 803
• Main Authors: Hollstein, Ronja, Parry, David A, Nalbach, Lisa, Logan, Clare V, Strom, Tim M, Hartill, Verity L, Carr, Ian M, Korenke, Georg C, Uppal, Sandeep, Ahmed, Mushtaq, Wieland, Thomas, Markham, Alexander F, Bennett, Christopher P, Gillessen-Kaesbach, Gabriele, Sheridan, Eamonn G, Kaiser, Frank J, Bonthron, David T
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.12.2015; BMJ Publishing Group
• Series: Original article
• Subjects: Cells, Cultured; Child; Child, Preschool; DNA Mutational Analysis; Families & family life; Female; Fibroblasts; Genes; Genes, Recessive; Genetic testing; Genomes; Humans; Infant; Male; Mutation; Neurodevelopmental Disorders - genetics; New Loci; Patients; Pedigree; Polymorphism, Single Nucleotide; Spasticity; Syndrome; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics; United States > US; California; Genetics
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2015-103344

BackgroundThe genetic aetiology of neurodevelopmental defects is extremely diverse, and the lack of distinctive phenotypic features means that genetic criteria are often required for accurate diagnostic classification. We aimed to identify the causative genetic lesions in two families in which eight affected individuals displayed variable learning disability, spasticity and abnormal gait.MethodsAutosomal recessive inheritance was suggested by consanguinity in one family and by sibling recurrences with normal parents in the second. Autozygosity mapping and exome sequencing, respectively, were used to identify the causative gene.ResultsIn both families, biallelic loss-of-function mutations in HACE1 were identified. HACE1 is an E3 ubiquitin ligase that regulates the activity of cellular GTPases, including Rac1 and members of the Rab family. In the consanguineous family, a homozygous mutation p.R219* predicted a truncated protein entirely lacking its catalytic domain. In the other family, compound heterozygosity for nonsense mutation p.R748* and a 20-nt insertion interrupting the catalytic homologous to the E6-AP carboxyl terminus (HECT) domain was present; western blot analysis of patient cells revealed an absence of detectable HACE1 protein.ConclusionHACE1 mutations underlie a new autosomal recessive neurodevelopmental disorder. Previous studies have implicated HACE1 as a tumour suppressor gene; however, since cancer predisposition was not observed either in homozygous or heterozygous mutation carriers, this concept may require re-evaluation.