ITGB6 loss-of-function mutations cause autosomal recessive amelogenesis imperfecta

Abstract

Integrins are cell-surface adhesion receptors that bind to extracellular matrices (ECM) and mediate cell-ECM interactions. Some integrins are known to play critical roles in dental enamel formation. We recruited two Hispanic families with generalized hypoplastic amelogenesis imperfecta (AI). Analysis of whole-exome sequences identified three integrin beta 6 (ITGB6) mutations responsible for their enamel malformations. The female proband of Family 1 was a compound heterozygote with an ITGB6 transition mutation in Exon 4 (g.4545G > A c.427G > A p.Ala143Thr) and an ITGB6 transversion mutation in Exon 6 (g.27415T > A c.825T > A p.His275Gln). The male proband of Family 2 was homozygous for an ITGB6 transition mutation in Exon 11 (g.73664C > T c.1846C > T p.Arg616*) and hemizygous for a transition mutation in Exon 6 of Nance-Horan Syndrome (NHS Xp22.13; g.355444T > C c.1697T > C p.Met566Thr). These are the first disease-causing ITGB6 mutations to be reported. Immunohistochemistry of mouse mandibular incisors localized ITGB6 to the distal membrane of differentiating ameloblasts and pre-ameloblasts, and then ITGB6 appeared to be internalized by secretory stage ameloblasts. ITGB6 expression was strongest in the maturation stage and its localization was associated with ameloblast modulation. Our findings demonstrate that early and late amelogenesis depend upon cell-matrix interactions. Our approach (from knockout mouse phenotype to human disease) demonstrates the power of mouse reverse genetics in mutational analysis of human genetic disorders and attests to the need for a careful dental phenotyping in large-scale knockout mouse projects.

Critical roles for WDR72 in calcium transport and matrix protein removal during enamel maturation

“…2014b). After embedded in paraffin, the tissues were sectioned at 5  μ m thickness, and the sections underwent regular immunostaining and imaging processing (Wang et al.…”

Expansion of the spectrum of ITGB6-related disorders to adolescent alopecia, dentogingival abnormalities and intellectual disability

“…14 Hair loss due to ITGB6 variants has not been reported in humans, which may be due to the young age of previously ascertained probands. 11,12 Adolescent alopecia was observed in affected individuals from family AP91, consistent with juvenile baldness on the head and neck of Itgb6 −/− mice. 15 Although a previously reported AI child who is homozygous for a stop-gain ITGB6 variant seemed to have average intelligence despite being suspected of having Nance-Horan syndrome 11 (MIM 302350), all three adult affected individuals in this report were confirmed to have mild-to-moderate intellectual disability by formal testing.…”

“…15 The occurrence of AI in knockout mice and in children o10 years old was supported by enamel defects seen by electron microscopy. [11][12][13] Likewise the three adult affected individuals from family AP91 had tooth loss, yellowish-brown staining, malocclusion, poor alignment and/or rough enamel, all of which may be AI-related. In addition the affected AP91 family members had severe periodontal disease, which was also observed in Itgb6 −/− mice.…”

“…ITGB6 variants were previously shown to cause amelogenesis imperfecta (AI) in young children, 11,12 and Itgb6-knockout mice present with enamel defects, 13 periodontal disease 14 and juvenile baldness. 15 The occurrence of AI in knockout mice and in children o10 years old was supported by enamel defects seen by electron microscopy.…”

Triagem de mutações e polimorfismos de genes candidatos à malformação dentária em pacientes com fissura labiopalatinas

“…De acordo com a literatura, os principais genes envolvidos na formação do esmalte dentário são: amelogenina ligado ao X (AMELX), enamelina (ENAM), ameloblastina (AMBN), metaloprotease da matriz-20 (MMP-20) e calicreína-4 (KLK-4) (STEPHANOPOULOS; GAREFALAKI; LYROUDIA, 2005;WRIGHT et al, 2009;WRIGHT et al, 2011). Recentes análises genéticas têm identificado mutações em FAM83H (KIM et al, 2008), WDR72 (EL-SAYED et al, 2009;LEE et al, 2010), FAM20A (O'SULLIVAN et al, 2011CHO et al, 2012), C4orf26 (PARRY et al, 2012, SLC24A4 (PARRY et al, 2013), LAMB3 (KIM et al, 2013;POULTER et al, 2014b;WANG et al, 2015) e ITGB6 (POULTER et al, 2014a;WANG et al, 2014 Apesar dos defeitos na formação do esmalte dentário não compreenderem um problema de saúde pública, podem causar alterações estéticas graves, além de comprometerem as estruturas do esmalte. As formas severas podem levar à perda precoce do esmalte, causando desgaste acentuado com prejuízo da função do órgão dentário.…”