ESPE Yearbook of Paediatric Endocrinology

In Brief: These authors identify a frameshift truncating variant in the gene SPIN4 (Spindlin member 4) in a patient with skeletal overgrowth, hepatosplenomegaly and macrocephaly. Using state-of-the-art mouse models and histone peptide arrays, they delineate the underlying pathogenic mechanism and show that SPIN4 positively regulates Wnt signalling by functioning as an epigenetic reader.

Commentary: Generalized overgrowth disorders are characterized by increased cellular proliferation leading to tall stature, macrocephaly and organomegaly. Some known overgrowth disorders, such as Weaver syndrome and Sotos syndrome, are caused by mutations in genes that function as chromatin modifiers. This paper describes a novel mutation in the gene SPIN4 in a patient with generalized overgrowth. It shows that SPIN4 functions as an epigenetic reader by binding to modified histones and mediating downstream effects.

The proband was a 13-year-old boy who was born large for gestational age and had excessive linear growth (+4.5 to +5 SDS) with advanced bone age. Exome sequencing identified a hemizygous frameshift truncating variant in SPIN4 on the X chromosome. Using histone peptide arrays, normal SPIN4 protein was shown to bind modified histones, whereas this binding was abrogated by the identified SPIN4 variant. In mouse models harboring the SPIN4 truncating variants, skeletal and organ overgrowth was evident, thus replicating the human phenotype. Mutant mice showed expanded resting zone in the growth plate cartilage leading to increased cell proliferation and increased growth plate height. Wild-type SPIN4 induced Wnt signaling and suppressed cell proliferation in-vitro, whereas mutant SPIN4 did not. Further, growth plate chondrocytes lacking SPIN4 showed reduced basal Wnt signaling.

The study implicates SPIN4 gene, an epigenetic reader in, skeletal overgrowth. SPIN4 was shown to regulate body size in mice by binding modified histones on chromatin and mediating downstream effects through the activation of Wnt signaling. This is a novel overgrowth syndrome and another example of an overgrowth syndrome caused by mutation in an epigenetic regulator of gene expression, thus highlighting the importance of epigenetic mechanisms in growth and maybe specifically its role to limit body growth and prevent overgrowth.