SLC10A7 – Short Stature, Amelogenesis Imperfecta, and Skeletal Dysplasia with Scoliosis

Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis is a rare autosomal recessive disorder first delineated in 2018, characterized by pre- and postnatal growth retardation, variable facial dysmorphisms, enamel hypoplasia, progressive limb and spinal abnormalities. SLC10A7 encodes a ten-transmembrane-domain transporter implicated in glycosaminoglycan synthesis and calcium homeostasis. Pathogenic variants in SLC10A7 disrupt normal extracellular matrix formation and skeletal development, resulting in the syndromic phenotype.

A recent case report identified a novel homozygous nonsense mutation in exon 1 of SLC10A7 (c.100G>T (p.Gly34Ter)) segregating with typical short stature, amelogenesis imperfecta, and progressive scoliosis requiring seven spinal surgeries in a Han Chinese family (PMID:38037133). This patient exhibited a more severe skeletal phenotype than previously reported. To date, 12 cases of SLC10A7-related disease have been documented (PMID:38037133).

In a cohort of six unrelated individuals, homozygous LoF and missense variants in SLC10A7 were identified, including c.184G>T (p.Glu62Ter) and c.388G>A (p.Gly130Arg), all presenting with skeletal dysplasia and amelogenesis imperfecta (PMID:30082715). A separate study uncovered compound heterozygous variants—one missense (c.335G>A (p.Gly112Asp)) and one splice-site (c.722-16A>G)—in two siblings with low bone mineral density and AI, mirrored by reduced bone mineralization in zebrafish morphants (PMID:29878199). Additionally, a homozygous missense mutation c.908C>T (p.Pro303Leu) was found in a consanguineous family with a milder phenotype, highlighting allelic variability (PMID:31191616).

The inheritance pattern is autosomal recessive, with homozygous and compound heterozygous variants consistently co-segregating with disease. Segregation analysis in multiple consanguineous families confirms pathogenicity, including two affected sib pairs (PMID:29878199; PMID:31191616). Phenotypic penetrance appears complete for dental and skeletal abnormalities. No founder variants have been reported, and carrier frequency remains unknown due to the rarity of the condition.

Functional studies demonstrate reduced SLC10A7 protein expression in patient fibroblasts and defective glycosaminoglycan synthesis (PMID:30082715). Slc10a7–/– mice exhibit shortened long bones, growth plate disorganization, and enamel anomalies, recapitulating human features (PMID:30082715). Decreased heparan sulfate levels were observed in mouse cartilage and patient cells, while zebrafish morphants display impaired bone mineralization (PMID:29878199). Intracellular mislocalization of glycoproteins and altered calcium trafficking further corroborate the molecular mechanism.

Integration of genetic and experimental data establishes a definitive gene–disease relationship. SLC10A7 mutations reliably predict a syndromic skeletal disorder with amelogenesis imperfecta, guiding molecular diagnosis and early intervention. Recognition of AI as a sentinel feature can expedite genetic testing and inform surgical management of spinal deformities. Key take-home: SLC10A7 screening is indicated in patients presenting with amelogenesis imperfecta and progressive skeletal dysplasia with scoliosis.

References

• Orphanet Journal of Rare Diseases • 2023 • Identification of novel homozygous nonsense SLC10A7 variant causing short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis and surgical management of spine. PMID:38037133
• Nature Communications • 2018 • SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects. PMID:30082715
• Human Molecular Genetics • 2018 • Integrating glycomics and genomics uncovers SLC10A7 as essential factor for bone mineralization by regulating post-Golgi protein transport and glycosylation. PMID:29878199
• Frontiers in Genetics • 2019 • A New SLC10A7 Homozygous Missense Mutation Responsible for a Milder Phenotype of Skeletal Dysplasia With Amelogenesis Imperfecta. PMID:31191616

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