Original articleA novel c.2T > C mutation of the KDM5C/JARID1C gene in one large family with X-linked intellectual disability
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.
References (24)
- et al.
Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation
Am. J. Hum. Genet.
(2005) - et al.
RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3
Cell
(2007) - et al.
The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases
Cell
(2007) - et al.
A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay
Neurosci. Lett.
(2011) - et al.
High prevalence of SLC6A8 deficiency in X-linked mental retardation
Am. J. Hum. Genet.
(2004) - et al.
X-linked mental retardation
Nat. Rev. Genet.
(2005) - et al.
XLMR genes: update 2007
Eur. J. Hum. Genet.
(2008) - et al.
A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation
Nat. Genet.
(2009) - et al.
The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation
Nature
(2007) - et al.
A distinctive gene expression fingerprint in mentally retarded male patients reflects disease-causing defects in the histone demethylase KDM5C
Pathogenetics
(2010)
Sex-specific expression of the X-linked histone demethylase gene Jarid1c in brain
PLoS One
Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia
J. Med. Genet.
Cited by (36)
Epigenetic modifier G9a is involved in regulation of mouse tongue development
2024, Journal of Oral BiosciencesDNA methylation fingerprint of monozygotic twins and their singleton sibling with intellectual disability carrying a novel KDM5C mutation
2020, European Journal of Medical GeneticsCitation Excerpt :Our dataset presented an enrichment of 68 CpGs (p-value<0.0001, Table S1). A novel KDM5C frameshift variant was identified in three brothers presenting intellectual disability and short stature, and in their clinically normal mother, who had completely skewed X-inactivation, as also observed in other women heterozygous for KDM5C mutations (Õunap et al., 2012). This mutation resulted in a premature stop codon, and a predicted non-functional protein.
A novel mosaic 1q32.1 microduplication identified through Chromosome Microarray Analysis: narrowing the smallest critical region including KDM5B gene found associated with neurodevelopmetal disorders
2019, European Journal of Medical GeneticsCitation Excerpt :There are growing emerging data about the major role of histone lysine methyltransferases (KMTs) and demethylases (KDMs) in neurodevelopmental disorders, due to their involvement in gene expression regulation by chromatin modification (Faundes et al., 2018). Interestingly, within demethylase gene family, KDM5A has been demonstrated to be involved in autosomal recessive ID (Najmabadi et al., 2011) while KDM5C have been reported to be mutated in a syndromic form of X-linked mental retardation (Ounap et al., 2012; Brookes et al., 2015). A de novo splicing mutation (c.283A > G) in KDM5B gene has been recently detected by next-generating sequencing in an individual with syndromic ID (Athanasakis et al., 2014).
Sex Chromosome Effects on Male–Female Differences in Mammals
2018, Current BiologyOver-expression of XIST, the Master Gene for X Chromosome Inactivation, in Females With Major Affective Disorders
2015, EBioMedicineCitation Excerpt :Nevertheless, it is plausible that over-expression of XIST and some escapee genes may be a common mechanism underlying development of psychiatric disorders between the rare patients with aneuploid X chromosomes and a subset of the general population of female psychiatric patients with a normal karyotype. Among these escapee genes, KDM5C is particularly interesting since its haploinsufficiency causes mental retardation (Ounap et al., 2012; Fieremans et al., 2015) or mood disorder (Jensen et al., 2005) in females. Mutations of KDM5C generate much more severe mental retardation in males (Jensen et al., 2005; Rujirabanjerd et al., 2010).
Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features
2015, European Journal of Medical GeneticsCitation Excerpt :Female carriers are generally unaffected although learning disabilities are not uncommon [Jensen et al., 2005; Rujirabanjerd et al., 2010]. Moreover, 3 reports of carrier females with mild to moderate ID [Abidi et al., 2008; Rujirabanjerd et al., 2010; Tzschach et al., 2015] and two families with female carriers suffering from ID and additional clinical features have been described [Jensen et al., 2005; Ounap et al., 2012]. In the first syndromic ID family, one girl carrying a nonsense c.3864G→A (p.Trp1288Ter) mutation, had severe ID together with spasticity, epileptic seizures, short stature, microcephaly, hypermetropia, and small feet [Jensen et al., 2005].