Truncating Mutations of MAGEL2, a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis

Abstract

Arthrogryposis multiplex congenita (AMC) is characterized by the presence of multiple joint contractures resulting from reduced or absent fetal movement. Here, we report two unrelated families affected by lethal AMC. By genetic mapping and whole-exome sequencing in a multiplex family, a heterozygous truncating MAGEL2 mutation leading to frameshift and a premature stop codon (c.1996delC, p.Gln666Serfs∗36) and inherited from the father was identified in the probands. In another family, a distinct heterozygous truncating mutation leading to frameshift (c.2118delT, p.Leu708Trpfs∗7) and occurring de novo on the paternal allele of MAGEL2 was identified in the affected individual. In both families, RNA analysis identified the mutated paternal MAGEL2 transcripts only in affected individuals. MAGEL2 is one of the paternally expressed genes within the Prader-Willi syndrome (PWS) locus. PWS is associated with, to varying extents, reduced fetal mobility, severe infantile hypotonia, childhood-onset obesity, hypogonadism, and intellectual disability. MAGEL2 mutations have been recently reported in affected individuals with features resembling PWS and called Schaaf-Yang syndrome. Here, we show that paternal MAGEL2 mutations are also responsible for lethal AMC, recapitulating the clinical spectrum of PWS and suggesting that MAGEL2 is a PWS-determining gene.

Figure 1

Truncating Mutation of Paternal MAGEL2 Allele in Family 1 and RNA Studies (a) Sequencing of DNA showing the MAGEL2 c.1996delC mutation in family 1 (I:2; II:2; III-1 to III-3). Arrows indicate mutant nucleotide position. (b) PCR analysis of MAGEL2 (1–4, 660 bp) and β-actin (5 and 6, 250 bp) in affected individuals (2, 4, and 6) and control individuals (1, 3, and 5) after reverse transcription (RT; 1 and 2) or without RT of RNA (3 and 4). Note the marked reduction of MAGEL2 in the affected individual (2) with respect to the control individual (1) and β-actin (5 and 6). MW, molecular weight. (c) Sequencing of the MAGEL2 RT-PCR products showing the paternally mutated allele only in the affected individual.

Figure 2

De Novo Truncating Mutation Occurring on the Paternal MAGEL2 Allele in Family 2 and RNA Studies (a) Sequencing of DNA showing the de novo MAGEL2 c.2118delT mutation in affected individual II:1. Arrows indicate mutant nucleotide position. Sequencing of MAGEL2 RT-PCR products (RNA) from affected individual II:1 revealed the mutated allele only. (b) Sequencing of DNA showing the rs2233070 polymorphism inherited from the mother (I:2 and II:1, arrow). Sequencing of MAGEL2 RT-PCR products (RNA) from affected individual II:1 revealed the paternal allele only.