First characterization of LTBP3 variants in two Moroccan families with hypoplastic amelogenesis imperfecta

Amelogenesis Imperfecta (AI) are inherited genetic disorders affecting the clinical structure, thickness and strength of enamel. Their prevalence varies according to the studied population from 1.4/1000 in Sweden (Bäckman & Holm, 1986) to 1/14000 in the USA (Kim et al., 2008). According to the amelogenesis stage, AI can be expressed by different phenotypes such a hypomature, hypocalcified, hypoplastic and hypomature-hypoplastic (Koruyucu et al., 2018, Witkop, 1988).

The Hypoplastic Amelogenesis Imperfecta (HAI), a quantitative enamel defect, represents 60–73% of AI cases (Nakata et al., 1985), and manifests as a low or reduced thickness enamel, characterized by the presence of pits or streaks; the enamel is nevertheless hard, translucent, sometimes with a rough or pitted appearance, giving the patient an unattractive appearance. The HAI can be isolated or associated with other symptoms, such as nephrocalcinosis and brachyolmia (Bloch-Zupan et al., 2012). The latter is a heterogeneous group of rare genetic skeletal disorders, characterized by short trunked and stature, with platyspondyly and scoliosis (Huckert et al., 2015).

One of the multiple causes of association of brachyolmia and HAI is the blockage of TGF-beta signaling, which leads to ameloblast inability to produce an enamel layer in incisors (Klopcic et al., 2007). Overexpression of TGF-beta1 in teeth results in ameloblast detachment and enamel defects (Crawford et al., 2007, Haruyama et al., 2006). Latent TGF-beta 1, 2 and 3 form a large complex with LTBP3 (Penttinen et al., 2002) and LTBP3 variants have been related to HAI associated with short stature and brachyolmia (OMIM 601216) in many populations (Huckert et al., 2015, Verloes et al., 1996).

The LTBP family contains 4 members (LTBP-1, LTBP-2, LTBP-3, and LTBP-4) (Todorovic & Rifkin, 2012). LTBP3 (NM_001130144.2) extends over 28 exons and encodes an extracellular matrix protein (NP_001157738.1) involved in regulating the secretion, uptake and activation of TGF-beta (Hyytiäinen et al., 2004, Klopcic et al., 2007). The LTBP3 protein has 3 types of domains: an epidermal growth factor (EGF) like calcium-binding domain, a TGF-beta-binding protein-like domain and an EGF like-domain (Robertson et al, 2011). LTBP3 is also involved in bone formation and remodeling, while its inhibition reduces the TGF-beta activation, and consequently decreases the associated cell proliferation and osteogenic differentiation (Koli et al., 2008).

LTBP3 variants are implicated in HAI pathologies (Flex et al., 2021), but none was described in Moroccan and North African populations. In this study, using whole exome sequencing, we identified the first LTBP3 pathogenic variants in three patients of two consanguineous Moroccan families with hypoplastic AI.

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