In recent years, mutations in genes related to osteoblast differentiation have been shown to be associated with OI. One gene that plays an important role at the osteoblast level is CREB3L1, encoding the old astrocyte specifically induced-substance (OASIS), which is subject to autosomal recessive mutations leading to Sillence type XVI OI. To date, CREB3L1/OASIS defects have been reported in only 5 OI families or individuals. In one Lebanese family, an in-frame deletion of a single-residue codon (P.lys312del) resulted in a mild phenotype (fracture, blue sclera) in heterozygotes, and this mutation caused prenatal/perinatal lethal OI in pure heterozygotes, similar to Sillence type II OI, as a result of mutations in the type I collagen gene [
32]. In the presence of endoplasmic reticulum stress, OASIS is translocated from the endoplasmic reticulum to the Golgi membrane and cleaved by the regulated intramembrane proteolysis (RIP) system, releasing the amino-terminal structural domain for transfer to the nucleus for further induction of target gene transcription [
33‐
35]. The RIP system is a highly conserved cellular signaling mechanism consisting of the endopeptidases S1P and S2P on the Golgi apparatus and is associated with growth, differentiation, and endoplasmic reticulum stress responses [
36]. Mutations in the MBTPS2 gene encoding S2P cause OASIS to be inactivated by cleavage, resulting in X-linked recessive Sillence type XVIII OI. Moderately severe X-linked recessive OI was reported in two independent lines from Thailand and Germany due to missense mutations in the MBTPS2 gene encoding S2P [
37]. WNT1 is a secreted ligand that binds to the low-density lipoprotein receptor-related proteins 5/6 (LRP5/6) and Frizzled receptor on osteoblast precursor cells to stimulate transcription of genes related to osteoblast differentiation via the β-catenin signaling pathway [
38]. Heterozygous mutations in the WNT1 gene cause osteoporosis and homozygous mutations cause Sillence type XV OI [
39]. Sillence Type XV OI is characterized by short stature, multiple vertebral compression fractures, kyphosis, and severe long bone fractures with phenotypic severity ranging from moderate to progressive deformity. About half of the patients with WNT1-related OI have neurological or brain abnormalities, including dilated ventricles with atrophic changes, cerebellar hypoplasia with short midbrain or type I Chiari malformation, and about 40% have severe intellectual disability or developmental delay [
40]. A striking feature is the asymmetry of microcephaly that can be observed in some patients. In addition, all patients with developmental delays or neurological deficits exhibited bilateral ptosis, a unique finding that may contribute to the diagnosis of WNT1-OI [
40]. The SP7 gene encodes an osteoblast-specific transcription factor (Osterix) necessary for bone formation and is a target gene of the WNT1 pathway. Mice with deletion of the SP7 gene exhibit insufficient osteoblast differentiation and reduced expression of osteoblast markers, and autosomal recessive mutations in this gene result in Sillence type XII OI [
41] (Fig.
2).