SOST – Sclerosteosis

Sclerosteosis is a rare, autosomal recessive craniotubular hyperostosis marked by excessive bone formation, tall stature, facial asymmetry, syndactyly, hearing impairment, and generalized osteosclerosis. The condition arises from biallelic loss-of-function mutations in the SOST gene, which encodes sclerostin, a secreted antagonist of Wnt signaling in osteoblasts. Sclerostin normally binds LRP5/6 to inhibit osteoblastic bone formation, and its absence leads to unchecked Wnt-driven bone deposition (PMID:20583295).

Linkage analysis in two consanguineous families mapped sclerosteosis to chromosome 17q12–q21, the interval harboring SOST, establishing the gene–disease relationship (PMID:10330353). A separate study identified a 52 kb downstream deletion in van Buchem disease, a clinically similar hyperostosis, implicating cis-regulatory elements of SOST (PMID:11836356). These studies provided definitive positional cloning evidence for SOST in human bone dysplasias.

The first pathogenic SOST variant, c.499T>C (p.Cys167Arg), was discovered in a Turkish family; this missense mutation disrupts the terminal cysteine of the cystine-knot motif, causing endoplasmic reticulum retention and abolishing LRP5 binding (PMID:20583295). Subsequent case reports identified six additional homozygous loss-of-function variants—frameshifts (c.296dup (p.Val100fs), c.87dup (p.Lys30fs), c.387delG (p.Asp131ThrfsTer116)), nonsense mutations (c.79C>T (p.Gln27Ter), c.371G>A (p.Trp124Ter), c.444_445TC>AA (p.Cys148ProTer))—in at least eight unrelated probands from Turkish, Indian, Moroccan, Egyptian, Chinese, Mediterranean, and Italian origins (PMID:23079137; PMID:24594238; PMID:25984533; PMID:26283468; PMID:25835322; PMID:35208525; PMID:36481973).

Autosomal recessive inheritance is confirmed by homozygosity in consanguineous pedigrees and heterozygous carrier parents without phenotype. At least two additional affected siblings have been documented segregating pathogenic SOST alleles alongside unaffected relatives, reinforcing genotype–phenotype correlation. No biallelic missense variants with residual function have been reported, consistent with a loss-of-function mechanism.

Functional assays demonstrate that the p.Cys167Arg mutant sclerostin is retained in the endoplasmic reticulum, fails to bind LRP5, and cannot inhibit Wnt–β-catenin signaling in osteoblastic cells, confirming complete loss of antagonistic activity (PMID:20583295). Although no human rescue studies exist, Sost knockout mice recapitulate high bone mass phenotypes, supporting haploinsufficiency and absence-of-function as the pathogenic mechanism.

Collectively, genetic mapping, multiple independent loss-of-function SOST variants in unrelated families, segregation data, and concordant functional studies yield a Strong gene–disease association. The robust evidence base underpins molecular diagnosis, carrier screening, and genetic counseling for sclerosteosis, and highlights sclerostin as a therapeutic target for bone disorders.

References

• American Journal of Human Genetics • 1999 • Localization of the gene for sclerosteosis to the van Buchem disease-gene region on chromosome 17q12-q21 PMID:10330353
• Journal of Medical Genetics • 2002 • Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease PMID:11836356
• Human Mutation • 2010 • First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function PMID:20583295
• Bone • 2013 • Novel SOST gene mutation in a sclerosteosis patient and her parents PMID:23079137
• European Journal of Medical Genetics • 2014 • Novel SOST gene mutation in a sclerosteosis patient from Morocco: a case report PMID:24594238
• BioMed Research International • 2015 • A Novel Loss-of-Sclerostin Function Mutation in a First Egyptian Family with Sclerosteosis PMID:25984533
• Clinical Genetics • 2016 • Sclerosteosis caused by a novel nonsense mutation of SOST in a consanguineous family PMID:26283468
• Pediatric Radiology • 2015 • Sclerosteosis (craniotubular hyperostosis-syndactyly) with complex hyperphalangy of the index finger PMID:25835322
• Medicina (Kaunas, Lithuania) • 2022 • A Novel Mutation in a Gene Causes Sclerosteosis in a Family of Mediterranean Origin PMID:35208525
• Neurological Sciences • 2023 • Neurological manifestations in patients and disease carriers in an Italian family with osteosclerosis PMID:36481973

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