Recessive TBC1D24 Mutations Are Frequent in Moroccan Non-Syndromic Hearing Loss Pedigrees.

Mutations in the TBC1D24 gene are responsible for four neurological presentations: infantile epileptic encephalopathy, infantile myoclonic epilepsy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures) and NSHL (non-syndromic hearing loss). For the latter, two recessive (DFNB86) and one dominant (DFNA65) mutations have so far been identified in consanguineous Pakistani and European/Chinese families, respectively. Here we report the results of a genetic study performed on a large Moroccan cohort of deaf patients that identified three families with compound heterozygote mutations in TBC1D24. Four novel mutations were identified, among which, one c.641G>A (p.Arg214His) was present in the three families, and has a frequency of 2% in control Moroccan population with normal hearing, suggesting that it acts as an hypomorphic variant leading to restricted deafness when combined with another recessive severe mutation. Altogether, our results show that mutations in TBC1D24 gene are a frequent cause (>2%) of NSHL in Morocco, and that due to its possible compound heterozygote recessive transmission, this gene should be further considered and screened in other deaf cohorts

Schematic representation of the mutations responsible for non-syndromic hearing loss, in the TBC1D24 protein.

<p>The TDC and TLBc functional domains are represented on the TBC1D24 protein structure. The amino-acid changes identified in this work (in bold) and the published recessive and dominant mutations responsible for NHSL are shown on the top, while mutations responsible for DOORS syndrome, familial infantile myoclonic epilepsy, progressive myoclonus epilepsy and early-infantile epileptic encephalopathy-16 are shown below the protein structure.</p

Mutations in <i>TBC1D24</i> segregate with non-syndromic hearing loss.

<p>(A) Pedigrees of the two families are shown with the segregation of the mutations identified in <i>TBC1D24</i>. (B) Electrophoregrams showing the 4 heterozygote mutations identified in this work. C) Alignments of TBC1D24 sequences around the 4 mutated amino acids highlighted by red rectangles (<i>H</i>.<i>s</i>.: <i>Homo sapiens</i>; <i>M</i>.<i>m</i>.: <i>Mus musculus</i>; <i>G</i>.<i>g</i>.: <i>Gallus gallus</i>; X.l.: <i>Xenopus laevis</i>; D.r.: <i>Danio rerio</i>).</p

Characteristics of the novel mutations identified in <i>TBC1D24</i> gene.

<p>For each mutation, its position in the cDNA is given, as well as the amino-acid change, its reference number in NCBI database (rs ID), its frequency in NCBI and Exome Variant Server (EVS) database, and the predicted Sift, Polyphen-2 and Mutation Taster scores.</p><p>Characteristics of the novel mutations identified in <i>TBC1D24</i> gene.</p