Submission Details

ZNF143 was first reported in relation to autosomal recessive methylmalonic acidemia (MMA) with homocystinuria (HCU) in 2016 (Pupavac et al., PMID:27349184). As a transcription factor in the cobalamin (vitamin B12) pathway, ZNF143 dysfunction results in inborn errors of cobalamin metabolism. Patients with MMA-HCU experience developmental delays, seizure, feeding difficulties, anemia, ocular manifestations, and failure to thrive among other phenotypes (PMID:9266389). Other forms of methylmalonic aciduria and homocystinuria have been classified into complementation groups including cblC, cblD, cblF, cblX, cblJ (PMID:29862147).

2 variants (1 missense, 1 nonsense) that were reported in 1 proband (PMIDs: 27349184) were included in this curation. A 16-month old Hispanic male was reported to have a variety of severe phenotypes including developmental abnormalities, infantile spasms with intractable epilepsy, combined immunodeficiency, hearing loss, cortical blindness, and prolonged QT intervals. The proband’s lab values showed elevated urinary methylmalonic acid, increased serum methylmalonic acid, and increased serum total homocysteine which are consistent with MMA-HCU. Somatic cell analysis in patient fibroblasts complemented multiple groups including cblC, cblF, cblX, clbD, and cblJ. Whole exome sequencing revealed two variants, c.851T>G (p.Leu284Ter) and c.1019C>T (p.Thr340Ile), as well as a balanced inversion (46, XY, inv (5) (p14.2p15.1)). The proband had a normal microarray, and the balanced inversion was also present in the proband’s unaffected father. In patient fibroblasts, MMACHC expression was absent (PMID:27349184). No other probands with notable ZNF143 dysfunction were reported in the literature in association with MMA-HCU. The mechanism of pathogenicity is predicted to be loss of function.

This gene-disease relationship is also supported by biochemical evidence, functional alteration assays, model systems, and rescue experiments (PMIDs: 33845046, 9009278, 22268977, 22268977, 27349184, 27349184). First, ABCD4 encodes a protein with a similar function, as it is a transporter in the cobalamin metabolism pathway. ABCD4 is implicated in a similar disease, methylmalonic acidemia with homocystinuria type cblJ, and was classified as moderate by the General IEM GCEP (PMID:33845046). Next, ZNF143 activates transcription of mRNA promoters when transfected into Drosophila cells. This demonstrates the biochemical function of ZNF143 as a transcription factor (PMID:9705341) and aligns with its predicted role as an activator of MMACHC expression. Functional alteration in non-patient cells was observed when MMACHC expression was significantly reduced in control fibroblasts treated with ZNF143 siRNA knockdown (PMID:27349184). In patient fibroblasts, a higher percentage of transcobalamin (TC) bound Cbl was found in subcellular compartments (ex.lysosomes, mitochondria) rather than cytoplasmic compartments compared to controls (PMID:27349184). GTEx analysis showed that ZNF143 is expressed in almost all tissues, which is consistent with its role as a transcription factor. Although this evidence was evaluated for expression evidence A, it was not scored due to lack of specificity in tissue type. Finally, Halbig et al. created a zebrafish model using morpholino knockdown of ZNF143. The zebrafish demonstrated a variety of developmental abnormalities also seen in human MMA-HCU patients such as structural abnormalities within the heart, ear, and brain. The developmental abnormalities were rescued by injecting a wildtype copy of zebrafish ZNF143 mRNA (PMID: 22268977).

In summary, ZNF143 is moderately associated with autosomal recessive methylmalonic acidemia with homocystinuria. Additional case reports will be required to reach a higher classification of this gene-disease relationship. This classification was approved by the ClinGen General Inborn Errors of Metabolism on the meeting date 12/8/2023 (SOP Version 10).