HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome

Abstract

Background: The 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.

Methods: Autosomal 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.

Results: In 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.

Conclusion: HACE1 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.

Keywords: Genetics.

Figure 1

(A) Simplified pedigree of family A. Affected individuals are shaded and numbered 1–5. The two deceased males with shaded symbols were reported to have been affected with clinical features similar to those of patients 1–4. Asterisks indicate individuals used for autozygosity mapping (C). Genotypes at position c.655 (reference sequence C, encoding arginine 219; mutant allele T) are shown. (B) Pedigree of family B. (C) Autozygosity mapping using the ‘heterozygous SNPs’ view of AutoSNPa. Heterozygous SNPs (Affymetrix GeneChip Mapping 10K Array) appear as black horizontal bars. Patients 1–4 have been assigned as affected, resulting in delineation of a 24 Mbp region of Chr.6 (pale blue shading) that was concordantly homozygous. Patient 5 also has an interval devoid of heterozygous SNPs within the same region (blue bar); the genotypes are again concordant in this subject (not shown). (D) Position of the truncating mutations within the domain structure of HACE1 and illustrative Sanger sequence electropherograms of genomic PCR amplicons. In family B, the segregation of the compound heterozygous mutations is shown. (E) Western blot analysis for HACE1 of cultured fibroblasts from patients 6 and 7.