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

Abstract

Alopecia with mental retardation (APMR) is a very rare disorder. In this study, we report on a consanguineous Pakistani family (AP91) with mild-to-moderate intellectual disability, adolescent alopecia and dentogingival abnormalities. Using homozygosity mapping, linkage analysis and exome sequencing, we identified a novel rare missense variant c.898G>A (p.(Glu300Lys)) in ITGB6, which co-segregates with the phenotype within the family and is predicted to be deleterious. Structural modeling shows that Glu300 lies in the β-propeller domain, and is surrounded by several residues that are important for heterodimerization with α integrin. Previous studies showed that ITGB6 variants can cause amelogenesis imperfecta in humans, but patients from family AP91 who are homozygous for the c.898G>A variant present with neurological and dermatological features, indicating a role for ITGB6 beyond enamel formation. Our study demonstrates that a rare deleterious variant within ITGB6 causes not only dentogingival anomalies but also intellectual disability and alopecia.

Figure 1

Pedigree drawing, clinical information and chromatograms from family AP91. (a) Pedigree of consanguineous family AP91 with intellectual disability, alopecia, progeroid appearance, periodontal disease and tooth abnormalities co-segregating with the ITGB6 c.898G>A (p.(Glu300Lys)) variant. (b) Photographs of affected individuals IV-2, IV-3 and IV-6 at 40, 39 and 33 years of age, respectively. Note fine sparse scalp hair, sparse eyebrows and eyelashes and deeply set facial wrinkles. Women were veiled because of religious beliefs. Affected male IV-2 had bilateral super-eruption of maxillary lateral incisors, small central incisors and poor alignment of teeth. The affected youngest sister IV-6 also had misaligned mandibular anterior teeth with rough surfaces. Both IV-2 and IV-6 had prominent yellowish-brown tooth stains and severe gingival disease. Individual IV-3 had no remaining teeth. (c) Chromatograms from homozygous affected and heterozygous/wildtype unaffected family members.

Figure 2

Protein sequence alignment, molecular modeling and ITGB6 expression. (a) The glutamic acid at position 300 (E300) of the human sequence is identical across 51 vertebrate species, including 36 mammals, five birds, three reptiles, one amphibian and six fish, and lies within a highly conserved region that includes His275 to Ser304 of human ITGB6. (b) Molecular modeling predicts a more buried configuration due to the p.Glu300Lys change and slight torsional adjustments on the hairpin loop within the β-propeller domain. (c) RT-PCR of commercially obtained human cDNA shows ITGB6 expression in adult brain but not in fetal brain. Control denotes no template. Forward 5′-GAGGGGAAAACCATCATTCA-3′ and reverse 5′-GTAGGACAACCCCGATGAGA-3′ primers for ITGB6 exon 3 were used. ClinVar accession number for the ITGB6 variant is SCV000249619.