Genetic basis of hyperlysinemia

Abstract

Background: Hyperlysinemia is an autosomal recessive inborn error of L-lysine degradation. To date only one causal mutation in the AASS gene encoding α-aminoadipic semialdehyde synthase has been reported. We aimed to better define the genetic basis of hyperlysinemia.

Methods: We collected the clinical, biochemical and molecular data in a cohort of 8 hyperlysinemia patients with distinct neurological features.

Results: We found novel causal mutations in AASS in all affected individuals, including 4 missense mutations, 2 deletions and 1 duplication. In two patients originating from one family, the hyperlysinemia was caused by a contiguous gene deletion syndrome affecting AASS and PTPRZ1.

Conclusions: Hyperlysinemia is caused by mutations in AASS. As hyperlysinemia is generally considered a benign metabolic variant, the more severe neurological disease course in two patients with a contiguous deletion syndrome may be explained by the additional loss of PTPRZ1. Our findings illustrate the importance of detailed biochemical and genetic studies in any hyperlysinemia patient.

Figure 1

Molecular and biochemical studies in hyperlysinemia patients. (A) Schematic representation of the lysine degradation pathway. Lysine can be degraded via two pathways. The pathway with L-pipecolic acid as an intermediate operates in brain and starts with oxidative deamination. The main pathway in other organs, however, proceeds via deamination with saccharopine as an intermediate. All genes known to operate in this pathway are indicated. ALDH7A1 is deficient in children with pyridoxine-dependent seizures [3]. GCDH is deficient in glutaric aciduria type 1 [4]. The intermediate 2-oxoadipate is metabolized by 2-oxoadipate dehydrogenase, resembling the TCA cycle enzyme complex 2-oxoglutarate dehydrogenase. The E1 subunit of this complex is encoded by DHTKD1 and is deficient in 2-aminoadipic and 2-oxoadipic aciduria [5]. (B) Immunoblot analysis of fibroblast homogenates of hyperlysinemia cases. Cell lysates of 2 control subjects and hyperlysinemia cases were resolved by SDS-PAGE (30 μg of protein) blotted onto nitrocellulose and analyzed with a polyclonal antibody against AASS. (C) Relative expression levels of AASS in fibroblasts determined using qPCR with a primer sets specific for the 5^′ (R) and 3^′ (S) part of the cDNA. Average and SD are provided for 3 control fibroblasts. ND denotes not detectable. Expression was normalized to the level of cyclophilin B (PPIB). (D) Electropherogram showing that the heterozygous c.460G>A mutation in patient 5 appears homozygous at the cDNA level, indicating nonsense mediated decay of the other allele (c.2076dup).