Page 22 - Copper-associated hepatitis in the Labrador retriever diagnosis, treatment and genetics

Chapter 1
Wilson disease is caused by a wide variety of mutations in ATP7B. The clinical presentation in its hepatic or neurological form is highly variable, even among patients with the same mutation, which led several research groups to propose that this variation may be subject to other modulating genes29;104;105. As COMMD1 is known to interact with ATP7B and both proteins work in conjunction to facilitate copper excretion, it may be an interesting candidate modifier in patients with Wilson disease with an atypical presentation or in which no or only one mutation was detected. Several research groups screened their WD patient cohorts for mutations in COMMD1. Heterozygosity of a silent missense mutation c.492 GAT>GAC (Asp164Asp) in COMMD1 was reported to be possibly associated with an earlier onset of neurological manifestation of Wilson disease106, however, whereas this mutation was observed in other cohorts as well, an association with the phenotype could not be confirmed107-109. Several other mutations in COMMD1 were detected, but none of them was significantly correlated with variations of the disease phenotype103; 107; 108; 110; 111. Recently, a new mutation in COMMD1 was described in a patient with Wilson disease. This non-synonymous change c.521 ACGATG; Thr174Met resided in the recently identified NES (Nuclear Export Signal) region. The patient carrying this mutation was a compound heterozygote for WD mutations and exhibited extremely high urinary copper levels. In this case the COMMD1 mutation may have contributed to exaggeration of the disease phenotype109. Studies aiming to find COMMD1 mutations explaining the variability in WD are in general difficult to perform for two reasons. First, the diseases are rare and therefore recruitment of a large enough cohort is a challenge. Second, WD cohorts are heterogeneous with respect to mutations in the ATP7B gene and the clinical presentation. This makes it difficult to establish a relation between variations in COMMD1 and clinical manifestation of WD.
In conclusion, although there are indications that COMMD1 may be a modifying factor in human disorders of copper metabolism, there does not seem to be a major role. Thus far unknown genes involved in copper homeostasis may be responsible for the observed variation in disease phenotype.
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