A Novel Two-Nucleotide Deletion in the ATP7A Gene Associated With Delayed Infantile Onset of Menkes Disease

Abstract

BACKGROUND Determining the relationship between clinical phenotype and genotype in genetic diseases is important in clinical practice. In general, frameshift mutations are expected to produce premature termination codons, leading to production of mutant transcripts destined for degradation by nonsense-mediated decay. In X-linked recessive diseases, male patients with frameshift mutations typically have a severe or even lethal phenotype. PATIENT We report a case of a 17-month-old boy patient with Menkes disease (NIM#309400), an X-linked recessive copper metabolism disorder, caused by mutations in the ATP7A copper transporter gene. His clinical presentation involved unexpectedly late onset and milder symptoms. STUDY and RESULT His genomic DNA showed a de novo two-nucleotide deletion in exon 4 of ATP7A, predicting a translational frameshift and premature stop codon, and a classic severe phenotype. Characterization of his ATP7A mRNA showed no abnormal splicing. CONCLUSION We speculated that translation re-initiation could occur downstream of the premature termination codon, and produce a partially functional ATP7A protein. Study of the patient’s fibroblasts found no evidence of translation reinitiation, however the possibility remains that this phenomenon occurred in neural tissues and influenced the clinical phenotype.

Menkes disease diagnosed by a novel ATP7A frameshift mutation in a patient with infantile spasms—a case report

“…Presumably, translation reinitiation may have occurred. Translation re-initiation can occur downstream of the premature termination codon and produce a partially functional ATP7A protein (15,16). In this case, the onset of MD was late but the symptoms were typical, and might be similar with the researches from Wada T and Paulsen M (15,16), which is related to the residual function of ATP7A.…”

“…Translation re-initiation can occur downstream of the premature termination codon and produce a partially functional ATP7A protein (15,16). In this case, the onset of MD was late but the symptoms were typical, and might be similar with the researches from Wada T and Paulsen M (15,16), which is related to the residual function of ATP7A. However, whether hemizygous duplication mutation of our proband affects messenger ribonucleic acid splicing and the level of ATP7A expression or not is unknown.…”

An Assessment of GUCA1C Variants in Primary Congenital Glaucoma

“…We performed an in silico prediction of the start codons using NetStart 1.0 ( , accessed date 8 June 2020) [ 16 ] and found that the AUG at codon 28 is a probable translation start that has an even higher score (0.53) than the canonical start codon (0.43). Translation re-initiation has been shown to lead to hypomorphic or moderate clinical phenotypes in patients suffering from different inherited disorders [ 17 , 18 , 19 , 20 , 21 ]. How often translation re-initiation completely rescues the effect of nonsense variants is unknown, since these subjects would be asymptomatic.…”