Intragenic MBD5 familial deletion variant does not negatively impact MBD5 mRNA expression

Molecular Cytogenetics

Sarah H Elsea¹  Sureni V Mullegama¹ 

[1]Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB2015, Houston 77030, TX, USA

关键词: Familial variant;    Gene expression;    Intronic deletion;    5?UTR;    MBD5;    2q23.1 deletion syndrome;   

Others  :  1163003
DOI  :  10.1186/s13039-014-0080-9

 received in 2014-09-18, accepted in 2014-10-25,  发布年份 2014

【 摘 要 】

2q23.1 deletion syndrome is characterized by intellectual disability, speech impairment, seizures, disturbed sleep pattern, behavioral problems, and hypotonia. Core features of this syndrome are due to haploinsufficiency of MBD5. Deletions that include coding and noncoding exons show reduced MBD5 mRNA expression. We report a patient with a neurological and behavioral phenotype similar to 2q23.1 deletion syndrome with an inherited intronic deletion in the 5-prime untranslated region of MBD5. Our data show that this patient has normal MBD5 mRNA expression; therefore, this deletion is likely not causative for 2q23.1 deletion syndrome. Overall, it is important to validate intronic deletions for pathogenicity.

【 授权许可】

   
2014 Mullegama and Elsea; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Shichiji M, Ito Y, Shimojima K, Nakamu H, Oguni H, Osawa M, Yamamoto T: A cryptic microdeletion including MBD5 occurring within the breakpoint of a reciprocal translocation between chromosomes 2 and 5 in a patient with developmental delay and obesity. Am J Med Genet A 2013, 161A:850-855.
• [2]Talkowski ME, Mullegama SV, Rosenfeld JA, van Bon BW, Shen Y, Repnikova EA, Gastier-Foster J, Thrush DL, Kathiresan S, Ruderfer DM, Chiang C, Hanscom C, Ernst C, Lindgren AM, Morton CC, An Y, Astbury C, Brueton LA, Lichtenbelt KD, Ades LC, Fichera M, Romano C, Innis JW, Williams CA, Bartholomew D, Van Allen MI, Parikh A, Zhang L, Wu BL, Pyatt RE, et al.: Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder. Am J Hum Genet 2011, 89:551-563.
• [3]Laget S, Joulie M, Le Masson F, Sasai N, Christians E, Pradhan S, Roberts RJ, Defossez PA: The human proteins MBD5 and MBD6 associate with heterochromatin but they do not bind methylated DNA. PLoS One 2010, 5:e11982.
• [4]Bonnet C, Ali Khan A, Bresso E, Vigouroux C, Beri M, Lejczak S, Deemer B, Andrieux J, Philippe C, Moncla A, Giurgea I, Devignes MD, Leheup B, Jonveaux P: Extended spectrum of MBD5 mutations in neurodevelopmental disorders. Eur J Hum Genet 2013, 21:1457-1461.
• [5]Williams SR, Mullegama SV, Rosenfeld JA, Dagli AI, Hatchwell E, Allen WP, Williams CA, Elsea SH: Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Eur J Hum Genet 2010, 18:436-441.
• [6]Hodge JC, Mitchell E, Pillalamarri V, Toler TL, Bartel F, Kearney HM, Zou YS, Tan WH, Hanscom C, Kirmani S, Hanson RR, Skinner SA, Rogers RC, Everman DB, Boyd E, Tapp C, Mullegama SV, Keelean-Fuller D, Powell CM, Elsea SH, Morton CC, Gusella JF, DuPont B, Chaubey A, Lin AE, Talkowski ME: Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities. Mol Psychiatry 2014, 19:368-379.
• [7]Cenik C, Derti A, Mellor JC, Berriz GF, Roth FP: Genome-wide functional analysis of human 5' untranslated region introns. Genome Biol 2010, 11:R29. BioMed Central Full Text
• [8]Krawczak M, Thomas NS, Hundrieser B, Mort M, Wittig M, Hampe J, Cooper DN: Single base-pair substitutions in exon-intron junctions of human genes: nature, distribution, and consequences for mRNA splicing. Hum Mutat 2007, 28:150-158.
• [9]Dabell MP, Rosenfeld JA, Bader P, Escobar LF, El-Khechen D, Vallee SE, Dinulos MB, Curry C, Fisher J, Tervo R, Hannibal MC, Siefkas K, Wyatt PR, Hughes L, Smith R, Ellingwood S, Lacassie Y, Stroud T, Farrell SA, Sanchez-Lara PA, Randolph LM, Niyazov D, Stevens CA, Schoonveld C, Skidmore D, MacKay S, Miles JH, Moodley M, Huillet A, Neill NJ, et al.: Investigation of NRXN1 deletions: clinical and molecular characterization. Am J Med Genet A 2013, 161A:717-731.
• [10]Ichikawa S, Sorenson AH, Imel EA, Friedman NE, Gertner JM, Econs MJ: Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria. J Clin Endocrinol Metab 2006, 91:4022-4027.
• [11]Ichikawa S, Tuchman S, Padgett LR, Gray AK, Baluarte HJ, Econs MJ: Intronic deletions in the SLC34A3 gene: a cautionary tale for mutation analysis of hereditary hypophosphatemic rickets with hypercalciuria. Bone 2014, 59:53-56.
• [12]Wang LL, Worley K, Gannavarapu A, Chintagumpala MM, Levy ML, Plon SE: Intron-size constraint as a mutational mechanism in Rothmund-Thomson syndrome. Am J Hum Genet 2002, 71:165-167.
• [13]van Kuilenburg AB, Meijer J, Mul AN, Meinsma R, Schmid V, Dobritzsch D, Hennekam RC, Mannens MM, Kiechle M, Etienne-Grimaldi MC, Klumpen HJ, Maring JG, Derleyn VA, Maartense E, Milano G, Vijzelaar R, Gross E: Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity. Hum Genet 2010, 128:529-538.