Inherited SHQ1 mutations impair interaction with NAP57/dyskerin, a major target in dyskeratosis congenita

Background: The inherited bone marrow failure syndrome dyskeratosis congenita (DC) is most frequently caused by mutations in DKC1 (MIM# 300126), the gene encoding NAP57 (aka dyskerin). The typically missense mutations modulate the interaction of NAP57 with its chaperone SHQ1, but no DC mutations have been identified in SHQ1 (MIM# 613663). Here, we report on two compound heterozygous mutations in SHQ1 in a patient with a severe neurological disorder including cerebellar degeneration. Methods: The SHQ1 mutations were identified by patient exome sequencing. The impact of the mutations was assessed in pulldown assays with recombinant NAP57. Results: The SHQ1 mutations were the only set of mutations consistent with an autosomal recessive mode of inheritance. The mutations map to the SHQ1-NAP57 interface and impair the interaction of the recombinant SHQ1 variants with NAP57. Conclusion: Intrauterine growth retardation and the neurological phenotype of the patient are reminiscent of the severe clinical variant of DC, the Hoyeraal-Hreidarsson syndrome (HH). Hence, SHQ1 screening may be warranted in patients with inherited bone marrow failure syndromes.