Original article
A novel c.2T > C mutation of the KDM5C/JARID1C gene in one large family with X-linked intellectual disability

https://doi.org/10.1016/j.ejmg.2012.01.004Get rights and content

Abstract

Mutations in the KDM5C gene (lysine (K)-specific demethylase 5C gene; also known as JARID1C and SMCX; MIM 314690) were recently associated with X-linked intellectual disability (XLID). To date only two case reports and five studies that screen for mutations in the KDM5C gene have been published, with 21 mutations reported. Herein we present a large family with XLID caused by a novel mutation c.2T > C in the start codon of the KDM5C gene, presumably leading to loss of gene translation. Six sibs out of seven (two sons and four sisters) and their mother carry this mutation. Two affected males presented the distinctive clinical phenotype, characterized by moderate short stature, clumsy gait, ataxia, increased muscle tone and brisk tendon reflexes. They constantly bore a happy and smiling facial expression, with a protruding tongue. We hereby offer the first thorough description of five affected females with the KDM5C gene mutation. Most frequent clinical features were short stature, facial dysmorphism and developmental problems. X-chromosome inactivation study showed completely skewed inactivation pattern of mutation-carrying chromosome in all affected female patients.

Highlights

► We describe a large family caused by the novel mutation c.2T > C in the KDM5C gene. ► We give the careful description of 5 affected females with the KDM5C gene mutation. ► Affected females had facial dysmorphism, developmental problems and short stature. ► We find completely skewed inactivation pattern of mutation-carrying X-chromosome.

Introduction

In the past 20 years great advances have been made in identifying the molecular basis of X-linked intellectual disability (XLID). Although the human X-chromosome carries only about 4% of the protein-coding genes in the human genome, X-linked gene defects are thought to be responsible for about 8–12% of the intellectual disability (ID) found in males [1]. Mutations in more than 80 genes have been associated with an XLID phenotype [1], [2], [3]. Jensen et al. [4] screened brain expressed genes from the Xp region in 210 families with XLID, and identified seven different mutations (nonsense, missense and frame-shift) in KDM5C (lysine (K)-specific demethylase 5C; also known as JARID1C or SMCX; MIM 314690) gene. This gene contains 26 exons and encodes a transcription factor that possesses several DNA binding motifs and shows histone demethylation activity specific for dimethylated and trimethylated lysine 4 of histone H3 [5], [6], [7]. KDM5C is expressed in all human tissues, including the brain, heart, skeletal muscles, liver, pancreas and lungs [4], [8]. Nevertheless, brain tissue, in particular fetal brain tissue, has higher levels of KDM5C transcript than other tissues [9].

Thus far five reported studies have highlighted the role of KDM5C as a cause of XLID [4], [10], [11], [12], [13]. Two additional case reports have been described [14], [15], bringing the total number of known mutations and described families to 21. We present a new large family with a novel mutation c.2T > C (g.1135T > C) in the start codon of the KDM5C gene.

Section snippets

III-9 (Fig. 1), 22-year-old male A.K.

He was born at term with a low birth weight of 2700 g (−2 SD), length 49 cm (−1 SD) and head circumference 34 cm (−1 SD). Apgar scores were 3/6/8. Developmental delay was noticed during the first year of life. At the age of 4.5 years a strong suspicion of Angelman syndrome (AS) was raised due to the following clinical features – severe developmental delay, profound speech impairment, ataxia, jerky movements, happy disposition with frequent laughing, protruding tongue, prognathia, strabismus,

Mutational analysis of KDM5C gene

The KDM5C gene consists of 26 exons and is located at Xp11.2. The KDM5C gene encodes seven transcripts, four of which are protein coding.

Genomic DNA was extracted, and the complete KDM5C coding sequence and adjacent splice sites were amplified on the Rotor-Gene 5-PLEX PCR cycling in 32 independent PCR reactions from genomic DNA. Following the PCR reaction, a High Resolution Melt (HRM) analysis in the presence of the Syto® 9 dye was performed. When an aberrant HRM pattern was detected, PCR

Results

In one large family with XLID a novel change (T > C) at nucleotide 2 in exon 1 of the KDM5C gene was found, resulting in a change in the start codon Methionine to Threonine (p.Met1Thr) (Fig. 1). This mutation was found in the mother, who passed it to two of her sons and four of her daughters, and was not identified in healthy family members. According to the NCBI Comparative Genomics Developments database, the beginning of exon 1 of the KDM5C gene is a highly conserved gene region. Based on

Discussion

In this paper we present a large family with XLID caused by a novel mutation c.2T > C in the KDM5C gene, affecting six sibs out of seven and their mother. In the described family two affected males presented a distinctive clinical phenotype characterized by a moderate short stature, clumsy gait, ataxia, increased muscle tone and brisk tendon reflexes (Fig. 3). Their faces bore a constantly happy and smiling appearance with a protruding tongue, especially when younger (Fig. 2). We summarized the

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

We would like to thank this family for their kind cooperation. We also acknowledge Prof. Ben Hamel from the Netherlands for his clinical advice and Kristin Eiklid from Norway. This work was performed through the NSW Genetics of Learning Disability Service and funded through NSW Health. This work was supported by GARLA grant 8175 from the Estonian Science Foundation and by Estonian Ministry of Education and Science grant no. 0180044s09.

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