Elsevier

Genomics

Volume 86, Issue 2, August 2005, Pages 182-194
Genomics

Characterization of a novel cation transporter ATPase gene (ATP13A4) interrupted by 3q25–q29 inversion in an individual with language delay

https://doi.org/10.1016/j.ygeno.2005.04.002Get rights and content

Abstract

Specific language impairment (SLI) is defined as failure to acquire normal language skills despite adequate intelligence and environmental stimulation. Although SLI disorders are often heritable, the genetic basis is likely to involve a number of risk factors. This study describes a 7-year-old girl carrying an inherited paracentric inversion of the long arm of chromosome 3 [46XX, inv(3)(q25.32–q29)] having clinically defined expressive and receptive language delay. Fluorescence in situ hybridization (FISH) with locus-specific bacterial artificial chromosome clones (BACs) as probes was used to characterize the inverted chromosome 3. The proximal and distal inversion breakpoint was found to reside between markers D3S3692/D3S1553 and D3S3590/D3S2305, respectively. ATP13A4, a novel gene coding for a cation-transporting P-type ATPase, was found to be disrupted by the distal breakpoint. The ATP13A4 gene was shown to comprise a 3591-bp transcript encompassing 30 exons spanning 152 kb of the genomic DNA. This study discusses the characterization of ATP13A4 and its possible involvement in speech-language disorder.

Introduction

Specific language impairment (SLI) is clinically characterized by delayed language development in the absence of other cognitive impairments. Individuals with SLI are assessed as having deficits of speech sound, expressive language, and comprehension of speech [1], [2], [3]. Many developmental cognitive disorders, such as mental retardation, autism, Attention Deficit disorder, or specific syndromes such as Down syndrome and Fragile X syndrome, may include delays in language development [2]. The genetics of language impairments has been well documented and many studies have demonstrated an increased frequency of language problems in individuals with first-degree relatives affected with language delay, compared with controls [4], [5]. In addition, twin studies have indicated a significant increase in MZ concordance rates compared with DZ rates [6], [7], suggesting that much of the familial aggregation can be attributed to genetic influences.

Little is known about the underlying molecular mechanisms of speech and language disorders. Genome-wide scans yield only weak results when attempts to identify potential risk loci are made, and there is often lack of reproduction between results obtained from different samples. To date, two genome screens have been performed. The first reported potential linkage on chromosome 16q24 and 19q13 [8], and the second implicated loci on chromosome 2p22 and 13q21 [9]. No risk gene has been identified so far as we know.

Recent studies support a genetic basis for SLI. A gene, FOXP2, which encodes a putative transcription factor, has been identified in the SPCH1 region of 7q31 in a three-generation family (named KE) with a severe speech and language disorder [2], [10], [11]. The disorder appears to be inherited in an autosomal dominant fashion. Individuals with a disruption of FOXP2 have difficulties with both expressive and receptive language [12], [13]. A separate study has also shown suggestive linkage of speech and language disorders to the long arm of chromosome 7 [14]. A relationship between autism and SLI has also been suggested because genetic studies in each disorder point to a locus on 7q31. The q31–q34 region of human chromosome 7 has been identified to contain a putative susceptibility locus for autism (AUTS1) [15], [16]. Language impairment is a major component of autistic disorders, but autistic individuals tend to have more severe language impairments compared with SLI patients [17]. Perhaps relevant to our study, a genome-wide scan in multiplex Finnish families affected with Asperger syndrome, an infantile autism, and developmental dysphasia provided evidence for a new autism locus on 3q25–q27 [18], [19].

In the present study, we describe a female with significant impairment in both expressive and receptive language abilities carrying an inversion on the chromosome 3q25–q29 inherited from her father, who was also language delayed. The chromosomal breakpoints of the inverted chromosome 3 have been investigated by fluorescence in situ hybridization (FISH), molecular genetic, and computational analyses. We describe the identification and characterization of a novel gene, ATP13A4, disrupted by the inversion, as a new member of a P5 ATPase family of proteins and a potential candidate gene for SLI.

Section snippets

Clinical report

The proband is a 7-year-old girl with a paracentric inversion, involving 3q25–q29, inherited from her father. The karyotype of proband and father was 46XX, inv(3)(q25–q29) and 46XY, inv(3)(q25–q29), respectively. She was born after an uncomplicated pregnancy and delivered at term. Weight at birth was 7 lb 3 oz. She is shy and quiet and has variability in her social communication skills. At a year and a half of age she had little speech. She started saying words at 2 years of age, phrases at 2

Patient collection and diagnostic ascertainment

The present study was approved by the Research Ethics Board of the Hospital for Sick Children and informed consent was obtained from the participants. The proband, a 7-year-old girl, was the only child of nonconsanguineous parents. Chromosome analysis from peripheral blood lymphocytes using G-banding showed paracentric inversion 46XX, inv(3)(q25–q29) (not shown). Cytogenetic analysis of peripheral blood was performed on the proband and her father. Diagnostic characterization, performed at 6

Acknowledgments

This study was supported by Genome Canada/Ontario Genomics Institute and the Hospital for Sick Children Foundation. We would like to thank Tero Ylisaukko-Oja, Lili Senman and Ying Qi for their help. Stephen W Scherer is an Investigator of the Canadian Institute of Health Research and an International Scholar of the Howard Hughes Medical Institute.

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