Identification of a novel splice mutation in CTNNB1 gene in a Chinese family with both severe intellectual disability and serious visual defects
- 235 Downloads
The CTNNB1 gene encode the β-catenin protein which is a core unit of the cadherin/catenin multiprotein complex. The loss-of-function mutation of the CTNNB1 gene recently has been confirmed as a cause of intellectual disability. Previous studies have found that patients with CTNNB1 gene mutation may have other clinical manifestation such as microcephaly, abnormal facial features, motor and language delays, and mild visual defects. Here, we reported a 27-year-old Chinese pregnant woman with a severe intellectual disability and serious visual defects who was detected with a novel splice mutation (c.734+1G>A) in CTNNB1 gene by whole-exome sequencing and confirmed by Sanger sequencing. Further investigation showed that the variant was inherited from her mother with similar phenotypes. This report not only helps to expand the mutant spectrum of the CTNNB1 gene but also prompts a new insight into genetic diagnosis in patients with both serious intellectual disability and visual defects.
KeywordsCTNNB1 gene Intellectual disability Visual defects Splice mutation
The CTNNB1 gene encodes the β-catenin protein which is a sub-unit of the cadherin/catenin multiprotein complex. Previous studies find CTNNB1 mutation related to several cancers . Recently, a large-scale sequencing firstly identified CTNNB1 loss-of-function mutations as the cause of intellectual disability (ID) . Other studies report different mutations in patients which phenotypes include ID, craniofacial anomalies, speech delay microcephaly, and mild visual disturbances like strabismus and hyperopia [3, 4, 5]. Our study describes a novel mutation of the CTNNB1 gene in a family who presented with serious ID and visual disturbances.
The neurologic examination found she had peripheral hypertonia with deep tendon hyperreflexia and Babinski sign positive, ataxic gait, and paroxysmal dystonic of head and neck, especially right-side rotation of head (Online Resource 1). Ceruloplasmin test, immunologic tests, brain MRI, and routine laboratory tests revealed nothing remarkable. Electroencephalograph (EEG) was mildly abnormal without typical epileptiform discharge and electromyography (EMG) was normal. Wechsler intelligence test showed severe ID with IQ score 28. The ophthalmologist found the woman had serious esotropia of both eyes, no reaction to light, and a complete lack of vision accompanied with nystagmus, lens, and vitreous opacities on oculus sinister. Complete retinal detachment and eyeball atrophy on her left eye were confirmed by fundus ultrasound.
(MP4 9892 kb)
For further investigation, whole-genome low-coverage sequencing (WGLCS) and whole-exome sequencing (WES) were performed to detect the potential pathogenic factors besides Karyotype (Online Resource 2). A novel mutation (c.734+1G>A) in the CTNNB1 gene was detected by WES and confirmed by Sanger sequencing (Fig. 1b).
(MP4 13,289 kb)
The splice mutation (c.734+1G>A) on CTNNB 1 gene has not been reported by any research or recorded by any related gene mutation database, such as HGMD, Clinvar, and LOVD and leads to a truncated CTNNB1 protein of 245 in comparison with the wide-type sequence of 781 amino acids. We performed three-dimensional modeling change of the truncated CTNNB1 protein (Fig. 2d), which loses the very important functional domain interactive with BCL9 (B cell CLL/lymphoma 9) and SCRIB indicated by Unipro database. As BCL9 and SCRIB both participate in the Wnt signaling pathway, so we infer that the splice mutation (c.734+1G>A) affect the structure and function of a β-catenin protein which may influence the Wnt signaling pathway and causing a series of clinical manifestations. So, our further research should elucidate how the mutation affects the function of β-catenin and the precise pathogenic molecular mechanisms.
The CTNNB1 gene encodes a β-catenin protein which is a central component of the cadherin/catenin complex. β-catenin protein participates in cell adhesion and nuclear signaling which mainly involves in the Wnt protein-mediated signal pathway. Previous studies declare CTNNB1 mutation is related to several cancers such as hepatocellular carcinoma, medulloblastoma, ovarian cancer, and pilomatricoma . It was firstly connected to ID since 2012 by De Ligt J  and then, a series of studies report more than 20 loss-function-mutations of the CTNNB1 gene which may lead to ID . As known, human β-catenin contains 781 amino acids and is subdivided into three domains: an amino-terminal domain (NTD), a central region containing 12 armadillo (ARM) repeats (residues 138–664), and a carboxy-terminal domain (CTD). However, by which mechanism, the truncated protein identified by this study may influence the Wnt signaling; it is worth further research.
Phenotypic characteristics of CTNNB1 mutation patients include ID, postnatal microcephaly, mild craniofacial particularities, and neurological disorders such as peripheral hypertonia, motor, and language development delay (Online Mendelian Inheritance in Man, OMIM# 615075). Mild visual disturbances were also reported such as astigmatism, hyperopia, and strabismus. Our case also indicated similar features but the proband suffers from complete retinal detachment and her mother also has severely impaired visual acuity. Panagiotou et al. found the CTNNB1 gene can result in exudative vitreoretinopathy with no neurological disorders . However, one 3-year-old Chinese boy initially presented with EVR showed facial dysmorphism and global developmental delay during follow-up and WES identified a de novo 1-bp insertion (c.1434_1435insC, Glu479ArgfsTer18) in CTNNB1 gene (OMIM *116806.0023). Niu Li et al. also reported a 15-month-old Chinese boy with retinal detachment and development delay, who was negative for mutation related to the exudative vitreoretinopathy but a heterozygous nonsense mutation (c.1627C>T, p. Gln558X) in CTNNB1 gene was found . Combined with our case, we suppose that CTNNB1 gene mutation not only can cause ID or EVR singly but also may synchronously result in these series phenotypes.
In conclusion, our study identifies a novel heterozygous splice mutation in the CTNNB1 gene (c.734+1G>A) in a Chinese family with both severe ID and visual disturbances. It helps to expand the mutant spectrum of the CTNNB1 gene and confirms that different types of mutation in CTNNB1 may be associated with ID and visual disturbances.
The authors would like to thank Guo Shunyuan, CHI Xin Chang, and Qiu Yaju for their comprehensive physical examination and critically reviewing of the manuscript. We are also grateful for all individuals who participated in this study.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Written informed consent was obtained from all individual participants included in the study for photograph and publication.
- 2.De Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE (2012) Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 367:1921–1929. https://doi.org/10.1056/NEJMoa1206524 CrossRefGoogle Scholar
- 3.Tucci V, Kleefstra T, Hardy A, Heise I, Maggi S, Willemsen MH, Hilton H, Esapa C, Simon M, Buenavista MT, McGuffin LJ, Vizor L, Dodero L, Tsaftaris S, Romero R, Nillesen WN, Vissers LE, Kempers MJ, Vulto-van Silfhout AT, Iqbal Z, Orlando M, Maccione A, Lassi G, Farisello P, Contestabile A, Tinarelli F, Nieus T, Raimondi A, Greco B, Cantatore D, Gasparini L, Berdondini L, Bifone A, Gozzi A, Wells S, Nolan PM (2014) Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features. J Clin Invest 124:1468–1482. https://doi.org/10.1172/JCI70372 CrossRefGoogle Scholar
- 4.Kuechler A, Willemsen MH, Albrecht B, Bacino CA, Bartholomew DW, van Bokhoven H, van den Boogaard MJ, Bramswig N, Büttner C, Cremer K, Czeschik JC, Engels H, van Gassen K, Graf E, van Haelst M, He W, Hogue JS, Kempers M, Koolen D, Monroe G, de Munnik S, Pastore M, Reis A, Reuter MS, Tegay DH, Veltman J, Visser G, van Hasselt P, Smeets EE, Vissers L, Wieland T, Wissink W, Yntema H, Zink AM, Strom TM, Lüdecke HJ, Kleefstra T, Wieczorek D (2015) De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum. Hum Genet 134:97–109. https://doi.org/10.1007/s00439-014-1498-1 CrossRefGoogle Scholar
- 6.Li N, Xu Y, Li G, Yu T, Yao R-e, Wang X, Wang J (2017) Exome sequencing identifies a de novo mutation of CTNNB1 gene in a patient mainly presented with retinal detachment, lens and vitreous opacities, microcephaly, and developmental delay: case report and literature review. Medicine 96:e6914. https://doi.org/10.1097/MD.0000000000006914 CrossRefGoogle Scholar
- 7.Panagiotou ES, Sanjurjo Soriano C, Poulter JA, Lord EC, Dzulova D, Kondo H, Hiyoshi A, Chung BHY, Chu YWY, Lai CHY, Tafoya ME, Karjosukarso D, Collin RWJ, Topping J, Downey LM, Ali M, Inglehearn CF, Toomes C (2017) Defects in the cell signaling mediator beta-catenin cause the retinal vascular condition FEVR. Am J Hum Genet 100:960–968. https://doi.org/10.1016/j.ajhg.2017.05.001 CrossRefGoogle Scholar
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.