Phenotypic Characterization of Intellectual Disability Caused by MBOAT7 Mutation in Two Consanguineous Pakistani Families

Abstract

A homozygous in-frame deletion (c. 758_778del; p. Glu253_Ala259del) in membrane-bound O-acyltransferase family member 7 (MBOAT7), also known as lysophosphatidylinositol acyltransferase (LPIAT1), was previously reported to be the genetic cause of intellectual disability (ID) in consanguineous families from Pakistan. Here, we identified two additional Pakistani consanguineous families with severe ID individuals sharing the same homozygous variant. Thus, we provide further evidence to support this MBOAT7 mutation as a potential founder variant. To understand the genotype-phenotype relationships of the in-frame deletion in the MBOAT7 gene, we located the variant in the fifth transmembrane domain of the protein and determined that it causes steric hindrance to the formation of an α-helix and hydrogen bond, possibly influencing its effectiveness as a functional transmembrane protein. Moreover, extensive neuropsychological observations, clinical interviews and genetic analysis were performed on 6 patients from the 2 families. We characterized the phenotype of the patients and noted the serious outcome of severe paraplegia. Thus, optimal management for symptom alleviation and appropriate screening in these patients are crucial.

Keywords: MBOAT7 gene; Pakistani consanguineous families; founder effect; in-frame deletion; intellectual disability.

Figure 1

Identification of a homozygous in-frame deletion in MBOAT7 in individuals with severe intellectual disability in Pakistani consanguineous families. (A) Pedigrees of consanguineous families of Family 1. (B) Pedigrees of consanguineous families of Family 2. A double bar represents parental consanguinity. Male subjects are represented by squares, female subjects by circles and affected individuals by shading; the arrow indicates the proband. Individuals who had undergone genetic testing are marked with an asterisk (+/+, wild type; +/–, heterozygous carrier; –/–, homozygous in-frame deletion). (C,D) Electropherogram showing the DNA sequence of the in-frame deletion variant (c.758_778del [p. Gln253_Ala259del]) in MBOAT7 (NM_024298.5, 2294 bp). (E) Genetic structure of MBOAT7. Mutations are indicated by arrows, and the in-frame deletion variant detected in the present work is indicated by a pentagram. (F) Location of the variant within the transmembrane domain of MBOAT7 protein (NP_077274.3, 472 amino acids) as shown in the red triangle (aa, amino acids).

Figure 2

Conservation analysis and molecular modeling of wild-type and mutant MBOAT7 protein. (A) Conservation analysis of the in-frame deletion variant (c.758_778del [p. Gln253_Ala259del]) in the MBOAT7 protein. MBOAT7 protein sequence alignment from different organisms indicates that the in-frame deletion variant is highly conserved in mammalian and vertebrate species: Homo sapiens (NP_077274.3), Bos taurus (NP_001068620.1), Mus musculus (NP_084210.2), Rattus norvegicus (NP_001128450.1), Pan troglodytes (XP_009434639.1), Xenopus tropicalis (XP_012822891.2), Oryctolagus cuniculus (DP001062.1). (B) Three-dimensional schematic of the structure of normal MBOAT7 protein (on the left) and the MBOAT7 protein with an in-frame deletion (p. Gln253_Ala259del) (on the right). The alteration in the three-dimensional positioning of the in-frame deletion causes steric hindrance to the formation of helices and hydrogen bonds in the MBOAT7 protein. The structure highlighted by the dotted box can be viewed magnified as indicated by the arrow. The red dots show hydrogen bonds.