Spectrum of ATP7B Gene Mutations in Pakistani Wilson Disease Patients: A Novel Mutation Is Associated with Severe Hepatic and Neurological Complication

Abstract

Wilson disease (WND) is an autosomal recessive disorder caused by mutation in ATP7B gene that impairs copper metabolism. ATP7B is involved in the transport of copper into the plasma protein ceruloplasmin and copper excretion out of the liver. Defects in ATP7B lead to excess of copper in various organs primarily in liver. The diagnosis of WND is more complex due to variations in its biochemical and clinical features and the broad range of disease onset. The objective of the present study was to establish molecular analysis system for screening of Wilson disease in Pakistani population. Three mutations were identified; with one being is a novel mutation never reported before.

Analysis of Wilson disease mutations in copper binding domain of ATP7B gene

“…However, two cases (WD-7 & WD10) that initially had only hepatic involvement later developed neuronal problems as well ( Table 2 ). Box plot shown in Fig 2 , demonstrates that patients presenting with only liver disease at the time of diagnosis had younger age of onset as compared to patients with both hepatic and neurological symptoms ( Fig 2 ), this data is consistent with previous report [ 10 ]. All patients without neurological symptoms are in their first or second decade of life and the possibility to develop neurological issues later in their lives could not be excluded [ 21 ].…”

“…Some of ATP7B variations appear to be population specific, while others are found in probands from variety of diverse ethnic families [ 20 , 22 , 23 ]. Mutational data from Asian countries is mainly available from China, Japan, South Korea and India [ 24 ] but there are only a few reports regarding molecular genetic screening performed on a total of 12WD cases from our Pakistani population [ 10 ].…”

“…Available at: http://www.hgmd.cf.ac.uk/ac/ index.php, Accessed: 17 May 2020) [5]. Owing to recessive inheritance pattern of WD, its incidence is higher in populations with customary consanguineous marriages like Pakistan, however only few variations have been reported from Pakistan (p.Cys271X, p.Val456L and p.V272V) necessitating comprehensive clinical and genetic studies on this disease from our local population [9][10][11].…”

PCR in Disease Diagnosis of WND

“…In present study, the siblings of index patients of WND were screened for mutations in ATP7B gene. We enrolled two families for genetic testing and novel mutation was described previously in one patient [25]. The past history of patients revealed the sudden onset of disease while no WND patient was reported earlier in these families.…”

“…The children of family 1 were born to non-consanguineous parents. History of patient belongs to family I was described earlier [25]. The children of family II were born to consanguineous parents.…”