A homozygous missense mutation inHERC2associated with global developmental delay and autism spectrum disorder

Abstract

We studied a unique phenotype of cognitive delay, autistic behavior, and gait instability segregating in three separate sibships. We initiated genome-wide mapping in two sibships using Affymetrix 10K SNP Mapping Arrays and identified a homozygous 8.2 Mb region on chromosome 15 common to five affected children. We used exome sequencing of two affected children to assess coding sequence variants within the mapped interval. Four novel homozygous exome variants were shared between the two patients; however, only two variants localized to the mapped interval on chromosome 15. A third sibship in an Ohio Amish deme narrowed the mapped interval to 2.6 Mb and excluded one of the two novel homozygous exome variants. The remaining variant, a missense change in HERC2 (c.1781C>T, p.Pro594Leu), occurs in a highly conserved proline residue within an RCC1-like functional domain. Functional studies of truncated HERC2 in adherent retinal pigment epithelium cells suggest that the p.Pro594Leu variant induces protein aggregation and leads to decreased HERC2 abundance. The phenotypic correlation with the mouse Herc1 and Herc2 mutants as well as the phenotypic overlap with Angelman syndrome provide further evidence that pathogenic changes in HERC2 are associated with nonsyndromic intellectual disability, autism, and gait disturbance. Hum Mutat 33:1639-1646, 2012. © 2012 Wiley Periodicals, Inc.

Complete loss of function of the ubiquitin ligase HERC2 causes a severe neurodevelopmental phenotype

“…Cranial magnetic resonance imaging studies was normal for one patient and showed a mild cerebral atrophy normal in one additional. 7 Clinical presentations of the seven patients were less severe than that of our patient, presumably because the mutated HERC2 protein conserved part of its activity. The homozygous deletion identified in our patient results in a complete absence of HERC2 protein that likely explains the severity of the developmental abnormalities.…”

“…HERC2 deletion could be associated to a more severe phenotype than missense mutation that was previously associated to autistic global developmental delay and autism spectrum disorder. 6,7 This report expands the spectrum of HERC2-related disease. Further studies are required to understand the link between ubiquitination defects and neurodevelopmental abnormalities.…”

“…A missense variant, (c.1781C4T, p.(Pro594Leu)), of the HERC2 gene was recently associated with an Angelman-like disorder in seven patients from the Old Order Amish community. 6,7 The phenotype observed in these patients included neonatal hypotonia, global developmental delay and gait instability. Cranial magnetic resonance imaging studies was normal for one patient and showed a mild cerebral atrophy normal in one additional.…”

“…Lately, a single homozygous mutation of HERC2 was found to segregate in Old Order Amish families with a neurodevelopmental disorder that has some phenotypic similarities to Angelman Syndrome. 6,7 Here we present a previously undescribed phenotype in an African patient presenting with OCA and a severe neurological and developmental disorder associated with a large homozygous deletion involving the two contiguous genes OCA2 and HERC2.…”

HERC2 Targets the Iron Regulator FBXL5 for Degradation and Modulates Iron Metabolism

“…It is a highly mutable gene located at a deletion breakpoint hot spot on human chromosome 15q11-q13 (27). A homozygous missense mutation of HERC2 is associated with a global developmental delay and autism spectrum disorder (28). Although the function of HERC2 had long remained unknown, the protein was recently shown to contribute to the response of cells to DNA damage.…”