Novel alteration in AMPD2 gene segregates with non-syndromic intellectual disability linked to MRT4 locus, conjointly responsible from Pontocerebellar hypoplasia

Abstract

Non-syndromic autosomal recessive intellectual disability(NS-ARID) withgenetic loci are listed with MRT numbering by Mendelian Inheritance ofMan (MIM). Since the discovery of the ����irst gene in MRT1, PRSS12, in 2002,to date a total of 34 loci and 17 genes are identi����ied. Only few of these genesare published causative in more than one family, while the rest are identi����iedin a single family that are characterized, disclosing the high heterogeneityof the genetic basis. MRT4 was published in 2007 in an examination of alarge consanguineous family with four affected members. The linked regionat 1p21.1-1p13.3 was 6.6 megabase commencing 78 genes. Exome sequencingof family members and ����iltering variations according to the pedigreedata revealed a single point mutation c.1526C>T, in AMPD2 gene, locatedat 1p13.3, altering uncharged polar amino acid threonine, at position 509,to nonpolar methionine (p.T509M), in evolutionally conserved adenosinedeaminase domain. This variation was not found in our in house exomesequencing of 150 Turkish individuals or in publically available SNP databases.Furthermore, this variation is assigned to be damaging by diverseprediction software analysis. AMPD2 plays a critical role in energy metabolism,functioning in purine metabolism by converting AMP to IMP via salvagepathways. Recently, deleterious mutations in AMPD2 gene are reportedin ����ive families with Pontocerebellar hypoplasia (PCH) with characteristicbrain imaging. Affected individuals in our family do not carry progressivecontext. We conclude that our case will expand the phenotypic spectrum ofdamaging AMPD2 mutations.