A boy with homozygous microdeletion of NEUROG1 presents with a congenital cranial dysinnervation disorder [Moebius syndrome variant]

Behavioral and Brain Functions

Julia C Schröder¹  Anne K Läßig⁴  Danuta Galetzka¹  Angelika Peters¹  John C Castle³  Stefan Diederich¹  Ulrich Zechner¹  Wibke Müller-Forell²  Annerose Keilmann⁴  Oliver Bartsch¹ 

[1] Institute of Human Genetics, University Medical Centre of the Johannes Gutenberg University Mainz, Langenbeckstrasse 1, D-55101, Mainz, Germany

[2] Institute of Neuroradiology, University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany

[3] TRON-Translational Oncology at the University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany

[4] Division of Communication Disorders, University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany

关键词: Autosomal recessive;    Homozygous deletion;    NEUROG1;    Aplasia/hypoplasia of cranial nerves V and VIII;    Aplasia/hypoplasia of cranial sensory ganglia;    Disorder of oral motor function;    Sensorineural deafness;    Mondini dysplasia;    Moebius syndrome variant;    Congenital cranial dysinnervation disorder;   

Others  :  793673
DOI  :  10.1186/1744-9081-9-7

 received in 2012-08-31, accepted in 2013-01-23,  发布年份 2013

【 摘 要 】

Background

We report on a 6-year-old Turkish boy with profound sensorineural deafness, balance disorder, severe disorder of oral motor function, and mild developmental delay. Further findings included scaphocephaly, plagiocephaly, long palpebral fissures, high narrow palate, low-set posteriorly rotated ears, torticollis, hypoplastic genitalia and faulty foot posture. Parents were consanguineous.

Methods and results

Computed tomography and magnetic resonance imaging showed bilateral single widened cochlear turn, narrowing of the internal auditory canal, and bilateral truncation of the vestibulo-cochlear nerve. Microarray analysis and next generation sequencing showed a homozygous deletion of chromosome 5q31.1 spanning 115.3 kb and including three genes: NEUROG1 (encoding neurogenin 1), DCNP1 (dendritic cell nuclear protein 1, C5ORF20) and TIFAB (TIFA-related protein). The inability to chew and swallow, deafness and balance disorder represented congenital palsies of cranial nerves V (trigeminal nerve) and VIII (vestibulo-cochlear nerve) and thus a congenital cranial dysinnervation disorder.

Conclusions

Based on reported phenotypes of neurog1 null mutant mice and other vertebrates, we strongly propose NEUROG1 as the causative gene in this boy. The human NEUROG1 resides within the DFNB60 locus for non-syndromic autosomal recessive deafness on chromosome 5q22-q31, but linkage data have excluded it from being causative in the DFNB60 patients. Given its large size (35 Mb, >100 genes), the 5q22-q31 area could harbor more than one deafness gene. We propose NEUROG1 as a new gene for syndromic autosomal recessive hearing loss and congenital cranial dysinnervation disorder including cranial nerves V and VIII.

【 授权许可】

   
2013 Schröeder et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Gutowski NJ, Bosley TM, Engle EC: 110th ENMC International Workshop: the congenital cranial dysinnervation disorders (CCDDs). Naarden, The Netherlands, 25–27 October, 2002. Neuromuscul Disord 2003, 13:573-578.
• [2]Oystreck DT, Engle EC, Bosley TM: Recent progress in understanding congenital cranial dysinnervation disorders. J Neuroophthalmol 2011, 31:69-77.
• [3]Webb JF, Noden DM: Ectodermal placodes: contributions to the development of the vertebrate head. Am Zool 1993, 33:434-447.
• [4]Schlosser G: Making senses development of vertebrate cranial placodes. Int Rev Cell Mol Biol 2010, 283:129-234.
• [5]Fischer T, Faus-Kessler T, Welzl G, Simeone A, Wurst W, Prakash N: Fgf15-mediated control of neurogenic and proneural gene expression regulates dorsal midbrain neurogenesis. Dev Biol 2011, 350:496-510.
• [6]Takano-Maruyama M, Chen Y, Gaufo GO: Differential contribution of Neurog1 and Neurog2 on the formation of cranial ganglia along the anterior-posterior axis. Dev Dyn 2012, 241:229-241.
• [7]Fode C, Gradwohl G, Morin X, Dierich A, LeMeur M, Goridis C, Guillemot F: The bHLH protein NEUROGENIN 2 is a determination factor for epibranchial placode-derived sensory neurons. Neuron 1998, 20:483-494.
• [8]Ma Q, Chen Z, del Barco Barrantes I, de la Pompa JL, Anderson DJ: Neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia. Neuron 1998, 20:469-482.
• [9]Ma Q, Fode C, Guillemot F, Anderson DJ: Neurogenin1 and neurogenin2 control two distinct waves of neurogenesis in developing dorsal root ganglia. Genes Dev 1999, 13:1717-1728.
• [10]Ma Q, Anderson DJ, Fritzsch B: Neurogenin 1 null mutant ears develop fewer, morphologically normal hair cells in smaller sensory epithelia devoid of innervation. J Assoc Res Otolaryngol 2000, 1:129-143.
• [11]Graham JM, Phelps PD, Michaels L: Congenital malformations of the ear and cochlear implantation in children: Review and temporal bone report of common cavity. J Laryngol Otol Suppl 2000, 25:1-14.
• [12]Langmead B, Trapnell C, Pop M, Salzberg SL: Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 2009, 10:R25. BioMed Central Full Text
• [13]Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, 1000 Genome Project Data Processing Subgroup: The sequence alignment/map format and SAM tools. Bioinformatics 2009, 25:2078-2079.
• [14]Ma Q, Kintner C, Anderson DJ: Identification of neurogenin, a vertebrate neuronal determination gene. Cell 1996, 87:43-52.
• [15]Sommer L, Ma Q, Anderson DJ: Neurogenins, a novel family of atonal-related bHLH transcription factors, are putative mammalian neuronal determination genes that reveal progenitor cell heterogeneity in the developing CNS and PNS. Mol Cell Neurosci 1996, 8:221-241.
• [16]Matsumura T, Semba K, Azuma S, Ikawa S, Gohda J, Akiyama T, Inoue J: TIFAB inhibits TIFA, TRAF-interacting protein with a forkhead-associated domain. Biochem Biophys Res Commun 2004, 317:230-234.
• [17]Matsumura T, Kawamura-Tsuzuku J, Yamamoto T, Semba K, Inoue J: TRAF-interacting protein with a forkhead-associated domain B (TIFAB) is a negative regulator of the TRAF6-induced cellular functions. J Biochem 2009, 146:375-381.
• [18]Kim Y, Park CS, Shin HD, Choi JW, Cheong HS, Park BL, Choi YH, Jang AS, Park SW, Lee YM, Lee EJ, Park SG, Lee JY, Lee JK, Han BG, Oh B, Kimm K: A promoter nucleotide variant of the dendritic cell-specific DCNP1 associates with serum IgE levels specific for dust mite allergens among the Korean asthmatics. Genes Immun 2007, 8:369-378.
• [19]Zhou T, Wang S, Ren H, Qi XR, Luchetti S, Kamphuis W, Zhou JN, Wang G, Swaab DF: Dendritic cell nuclear protein-1, a novel depression-related protein, upregulates corticotropin-releasing hormone expression. Brain 2010, 133:3069-3079.
• [20]Verzijl HT, van der Zwaag B, Cruysberg JR, Padberg GW: Moebius syndrome redefined: a syndrome of rhombencephalic maldevelopment. Neurology 2003, 61:327-333.
• [21]Terzis JK, Karypidis D: Direct tongue neurotization: the effect on speech intelligibility in patients with Moebius syndrome. Plast Reconstr Surg 2010, 125:150-160.
• [22]MacDermot KD, Winter R, Taylor D, Baraitser M: Oculofacialbulbar palsy in mother and son: review of 26 reports of familial transmission within the “Moebius spectrum of defects”. J Med Genet 1991, 28:18-26.
• [23]Kumar D: Moebius syndrome. J Med Genet 1990, 27:122-126.
• [24]Webb BD, Shaaban S, Gaspar H, Cunha LF, Schubert CR, Hao K, Robson CD, Chan WM, Andrews C, MacKinnon S, Oystreck DT, Hunter DG, Iacovelli AJ, Ye X, Camminady A, Engle EC, Jabs EW: HOXB1 founder mutation in humans recapitulates the phenotype of Hoxb1−/− mice. Am J Hum Genet 2012, 91:171-179.