MID1 mutations in patients with X-linked Opitz G/BBB syndrome

Abstract

Communicated by Arnold MunnichMutations in the MID1 gene are responsible for the X-linked form of Opitz G/BBB syndrome (OS), a disorder that affects the development of midline structures. OS is characterized by hypertelorism, hypospadias, laryngotracheo-esophageal (LTE) abnormalities, and additional midline defects. Cardiac, anal, and neurological defects are also present. The expressivity of OS is highly variable, even within the same family. We reviewed all the MID1 mutations reported so far, in both familial and sporadic cases. The mutations are scattered along the entire length of the gene and consist of missense and nonsense mutations, insertions and deletions, either inframe or causing frameshifts, and deletions of either single exons or the entire MID1 coding region. The variety of described mutations and the lack of a strict genotype-phenotype correlation confirm the previous suggestion of the OS phenotype being caused by a loss-of-function mechanism. However, although a specific mutation cannot entirely account for the observed phenotype, we observed preferential association between some types of mutation and specific clinical manifestations, e.g., brain anatomical defects and truncating mutations. This may suggest that the pathogenetic mechanism underlying the OS phenotype is more complex and may vary among the affected organs. Hum Mutat 29(5), [584][585][586][587][588][589][590][591][592][593][594] 2008.

X-linked microtubule-associated protein, Mid1, regulates axon development

“…Various mutations of MID1 have been identified in human patients with X-linked OS (25), and it has been reported as an E3 ligase for PP2Ac (13). However, the role of Mid1 in mammalian neural development and function is largely unknown.…”

Hypospadias associated with hypertelorism, the mildest phenotype of Opitz syndrome

“…As hypospadias forms part of OS, 8 we hypothesized that the gene responsible for the X-linked form of OS, the MID1 gene, might be involved in the development of hypospadias as a mild form of OS. 9,10 We identified one nonsense mutation, one missense mutation and two synonymous variants. We also found there was significant difference between the rare allele frequency of SNP c.1230G4A in cases as compared with controls.…”

“…Mutations in the MID1 gene cause the X-linked form of Opitz G/BBB syndrome (OS, characterized by midline abnormalities such as hypertelorism, cleft lip/palate, tracheo-esophageal abnormalities, cardiac defects and hypospadias). [8][9][10] The function of MID1 is highly conserved in vertebrates, and experiments conducted in mice and chicken showed that MID1 expression correlated well with the tissues affected in OS. 11,12 In situ hybridization studies on human embryos showed that the expression of MID1 was localized in undifferentiated cells of midline structures including the urogenital system.…”

“…13 Hypospadias is one common finding in OS cases (485%) with MID1 mutations, thus MID1 is a strong candidate gene for hypospadias. 10 The MID1 protein consists of 667 amino acids and belongs to the tripartite motif family. 14,15 The N-terminus of the protein is composed of a RING finger motif (R), two B-box zinc-fingers (B1 and B2) and a coiled coil region.…”

Análise por imagem do sistema nervoso central e do fenótipo de indivíduos brasileiros com síndrome de Optiz G/BBB

“…Com formas mais brandas acometendo as mulheres, as quais apresentam hipertelorismo sem malformações genitais, e sem evidência de transmissão homem-homem, aventou-se a hipótese de que a herança poderia ser ligada ao cromossomo X . Com a evolução dos estudos sindromológicos, o fenótipo referente à herança ligada ao X foi definitivamente estabelecido (ROBIN; OPITZ; MUENKE, 1996;MAY et al, 1997;QUADERI et al, 1997;DE FALCO et al, 2003;RUSSOLILLO;MERONI, 2008 MERONI, 2011).…”