Identification of novel compound heterozygous variants in the SLC30A7 (ZNT7) gene in two French brothers with stunted growth, testicular hypoplasia and bone marrow failure

Authors: Huang, Liping; YANG, ZHONGYUE - University Of California, Davis; Kirschke, Catherine; PROUTEAU, CLEMENT - University Of Angers; COPIN, MARIE-CHRISTINE - University Of Angers; BONNEAU, DOMINIQUE - University Of Angers; PELLIER, ISABELLE - University Of Angers; COUTANT, RGIS - University Of Angers; MIOT, CHARLINE - University Of Angers; ZIEGLER, ALBAN - University Of Angers

Submitted to: Human Molecular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/13/2023
Publication Date: 2/23/2023
Citation: Huang, L., Yang, Z., Kirschke-Schneide, C.P., Prouteau, C., Copin, M., Bonneau, D., Pellier, I., Coutant, R., Miot, C., Ziegler, A. 2023. Identification of novel compound heterozygous variants in the SLC30A7 (ZNT7) gene in two French brothers with stunted growth, testicular hypoplasia and bone marrow failure. Human Molecular Genetics. 32(12):2016-2031. https://doi.org/10.1093/hmg/ddad033.
DOI: https://doi.org/10.1093/hmg/ddad033

Interpretive Summary: Zinc is an essential trace mineral. Dietary zinc deficiency results in stunted growth, skin lesions, hypogonadism (delayed or lack of sexual development during puberty due to inadequate sex hormone production), and frequent infections in humans. Mice genetically lacking Slc30a7 suffer from mild zinc deficiency and are prone to development of prostate cancer and insulin resistance. Disease-causing mutations in the human SLC30A7 (ZNT7) gene have not been previously reported. SLC30A7 encodes for ZNT7, a zinc transporter responsible for zinc store inside cells for functions of many enzymes and gene regulatory factors that need zinc as a activating co-factor. Here we describe two-boy siblings from a French family with stunted growth, testicular hypoplasia (small and underdeveloped testes), and bone marrow failure (producing less blood cells to supply for the bloodstream in the bone marrow). Exome sequencing (DNA sequencing is performed in the genomic DNA regions that give information for protein production) revealed the presence of two different mutated DNA copies of ZNT7, namely compound heterozygous variants inherited from their mother and father. Molecular studies strongly suggest that the two mutations in SLC30A7 should be considered as a cause of growth retardation, testicular hypoplasia, and syndromic bone marrow failure.

Technical Abstract: Zinc is an essential trace mineral. Dietary zinc deficiency results in stunted growth, skin lesions, hypogonadism, and frequent infections in humans. Mice genetically lacking Slc30a7 suffer from mild zinc deficiency and are prone to development of prostate cancer and insulin resistance. Disease-causing mutations in the human SLC30A7 (ZNT7) gene have not been previously reported. Here we describe two-boy siblings from a French family with stunted growth, testicular hypoplasia, and bone marrow failure. Exome sequencing revealed compound heterozygous variants in ZNT7 consisting of NM_133496.5:c.21Adup; p.Asp8ArgfsTer3 and c.842+15T>C inherited from their unaffected mother and father, respectively. The c.21Adup variant led to a premature stop codon generated in exon 1 of the ZNT7 coding sequence. RNA-seq analysis demonstrated that the c.842+15T>C variant resulted in a leaky mRNA splicing event generating a premature stop codon right after the splicing donor site of exon 8. Moreover, the expression of ZNT7 protein was remarkably reduced by 61-94% in the affected brothers. These findings strongly suggest that biallelic variants in SLC30A7 should be considered as a cause of growth retardation, testicular hypoplasia, and syndromic bone marrow failure.