Immunodeficiency 47

A number sign (#) is used with this entry because of evidence that immunodeficiency-47 (IMD47) is caused by hemizygous mutation in the ATP6AP1 gene (300197) on chromosome Xq28.

Description

Immunodeficiency-47 is an X-linked recessive complex immunodeficiency syndrome characterized by recurrent bacterial infections, hypogammaglobulinemia, liver dysfunction, and defective glycosylation of serum proteins. Some patients may also have neurologic abnormalities (summary by Jansen et al., 2016).

Clinical Features

Jansen et al. (2016) reported 11 males from 6 unrelated families with a complex immunodeficiency disorder associated with liver disease. Five patients presented in infancy with signs of liver disease, including neonatal jaundice, hepatosplenomegaly, and abnormal liver function tests. Two patients presented in infancy with recurrent infections. The patients were initially ascertained from a cohort of patients with unexplained defective glycosylation of serum proteins, including abnormal N-glycosylation of transferrin, abnormal O-glycosylation of apolipoprotein CIII, and minor accumulations of truncated glycans. These findings were suggestive of defects in Golgi homeostasis and reminiscent of congenital disorders of glycosylation (see, e.g., CDG1A, 212065). All patients eventually developed recurrent bacterial infections associated with hypogammaglobulinemia, and some had poor response to childhood vaccinations. Laboratory studies showed leukopenia, abnormal liver enzymes, low serum copper and ceruloplasmin, and high alkaline phosphatase. Liver biopsies showed variable features that ranged in severity, and included steatosis, fibrosis, micronodular cirrhosis, and abnormal mitochondria. Six patients from 3 families who carried the same mutation (E346K; 300197.0003) had neurologic features, including seizures, mild intellectual disability, and behavioral abnormalities. Two of these 6 patients died of liver failure in early childhood. Three patients from another family had sensorineural hearing loss and hyperopia.

Inheritance

The transmission pattern of IMD47 in the families reported by Jansen et al. (2016) was consistent with X-linked recessive inheritance.

Molecular Genetics

In 11 males from 6 unrelated families with IMD47, Jansen et al. (2016) identified 4 different hemizygous missense mutations in the ATP6AP1 gene (300197.0001-300197.0004). The mutations, which were found by exome sequencing in most families, segregated with the disorder. Female carriers were unaffected. Transfection of 2 of the mutations (E346K, 300197.0003 and Y313C, 300197.0004) resulted in significant growth defects in yeast. Jansen et al. (2016) suggested that the variable systems affected in this disorder may result from tissue-specific processing of ATP6AP1, which could cause aberrant acidification and pH regulation, membrane trafficking and fusion, or abnormal glycosylation of proteins.