De novo heterozygous variants in SLC30A7 are a candidate cause for Joubert syndrome

Abstract

Joubert syndrome (JS), a well‐established ciliopathy, is characterized by the distinctive molar tooth sign on brain MRI, ataxia, and neurodevelopmental features. Other manifestations can include polydactyly, accessory frenula, renal, or liver disease. Here, we report individuals meeting criteria for JS with de novo heterozygous variants in SLC30A7 (Chr1p21.2). The first individual is a female with history of unilateral postaxial polydactyly, classic molar tooth sign on MRI, macrocephaly, ataxia, ocular motor apraxia, neurodevelopmental delay, and precocious puberty. Exome sequencing detected a de novo heterozygous missense variant in SLC30A7: NM_133496.5: c.407 T > C, (p.Val136Ala). The second individual had bilateral postaxial polydactyly, molar tooth sign, macrocephaly, developmental delay, and an extra oral frenulum. A de novo deletion–insertion variant in SLC30A7, c.490_491delinsAG (p.His164Ser) was found. Both de novo variants affect highly conserved residues. Variants were not identified in known Joubert genes for either case. SLC30A7 has not yet been associated with a human phenotype. The SLC30 family of zinc transporters, like SLC30A7, permit cellular efflux of zinc, and although it is expressed in the brain its functions remain unknown. Published data from proteomic studies support SLC30A7 interaction with TCTN3, another protein associated with JS. The potential involvement of such genes in primary cilia suggest a role in Sonic Hedgehog signaling. SLC30A7 is a candidate JS‐associated gene. Future work could be directed toward further characterization of SLC30A7 variants and understanding its function.

Structures, Mechanisms, and Physiological Functions of Zinc Transporters in Different Biological Kingdoms

“…It will also be interesting to see if another His residue in the His-loop can replace His164 for efficient Zn 2+ recruitment when His164 is deleted. Recently, a de novo heterozygous variant of SLC30A7 , His164Ser, was found in Joubert syndrome patients [ 130 ]. Although no SLC30A7 variants have yet been shown to cause human phenotypes or diseases, SLC30A7 is a candidate gene associated with Joubert syndrome [ 130 ].…”

“…Recently, a de novo heterozygous variant of SLC30A7 , His164Ser, was found in Joubert syndrome patients [ 130 ]. Although no SLC30A7 variants have yet been shown to cause human phenotypes or diseases, SLC30A7 is a candidate gene associated with Joubert syndrome [ 130 ].…”

Metalation and activation of Zn2+ enzymes via early secretory pathway-resident ZNT proteins

“…Both functions are required for Zn 2+ concentrations of ~60 nM in the medial Golgi and ~100 nM in the pre-cis Golgi. 35,36 These differences may explain why ZNT5-6 and ZNT7 have unique functional roles, which are reflected in the associated human genetic disorders, [37][38][39] although they are similar in terms of being required for enzyme maturation.…”