Content area

Full text

Correspondence to Dr Ohad S Birk, Ben-Gurion University of the Negev, POB 151 Beer-Sheva 84101, Israel; [email protected]

WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Sex-specific predilection and phenotypes in hereditary diseases caused by mutations in autosomal genes have been noted, yet the molecular mechanisms of these phenomena are poorly understood.

WHAT THIS STUDY ADDS

  • Through human and mouse studies, we show female-specific phenotypes due to ZNF142 mutation, elucidating downstream molecular mechanisms of this phenomenon.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • The study opens new venues of understanding molecular pathways of sex-specific phenotypes in hereditary diseases.

Introduction

Global developmental delay and epilepsy represent a large array of severe childhood neurological disorders with multiple causes, including monogenic mutations in zinc finger proteins.1–3 Recent studies, independent and parallel to ours, reported 36 individuals of 21 unrelated families with a neurological disorder of mild to moderate intellectual disability, with varying degrees of speech impairment and gross motor development, early onset seizures, hypotonia, behavioural features, movement disorders (tremor/dystonia) and facial dysmorphism. All affected individuals had likely pathogenic biallelic variants in ZNF142. While no functional studies were done in any of those reports, the ZNF142 variants were predicted to cause loss of function.2 4 5 Commensurate with the initial report of seven affected individuals—all females, of the 36 patients reported to date, the female-to-male ratio is 2:1.2 4 5

We now describe two females presenting with severe global developmental delay and epilepsy, apparent as of early childhood, due to a novel homozygous ZNF142 mutation. We delineate sex specificity with lower expression of the ZNF142 mouse ortholog, zfp142, in the wild-type female brain. Through generation and analysis of mice homozygous for a zfp142 mutation orthologous to the human mutation, we demonstrate that only female mutants showed a clear phenotype of hyper-locomotion and deficits in memory/learning. RNA-seq studies of the Zfp142 mutant mouse cerebellum, cortex and hippocampus demonstrated several differentially expressed genes (DEGs), most notably downregulation of Taok1 in the cortex and Mllt6 in the hippocampus.

Materials and methods

Subjects and clinical phenotyping

Blood samples were obtained from patients and healthy family members. DNA was extracted from peripheral blood leukocytes using FlexiGene DNA Extraction Kit (Qiagen) per manufacturer’s instructions. Clinical phenotyping was determined by experienced...

Show less