Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism, skeletal anomalies, and mental retardation

Abstract

We identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. The typical craniofacial dysmorphism included brachycephaly, highly arched bushy eyebrows, synophrys, long eyelashes, low-set ears, microdontism of primary teeth, and generalized gingival hyperplasia, whereas Sprengel deformity of scapula, fusion of spine, rib abnormities, pectus excavatum, and pes planus represented skeletal anomalies. The genome-wide homozygosity mapping using six affected individuals localized the disease gene to a 3.3-Mb region on chromosome 1q23.3-q24.1. Candidate gene sequencing identified a homozygous frameshift mutation, c.139_140delAG, in the transmembrane and coiled-coil domains 1 (TMCO1) gene, as the pathogenic change in all affected members of the extended pedigree. This mutation is predicted to result in a severely truncated protein (p.Ser47Ter) of only one-fourth the original length. The TMCO1 gene product is a member of DUF841 superfamily of several eukaryotic proteins with unknown function. The gene has highly conserved amino acid sequence and is universally expressed in all human tissues examined. The high degree of conservation and the ubiquitous expression pattern in human adult and fetal tissues suggest a critical role for TMCO1. This report shows a TMCO1 sequence variant being associated with a genetic disorder in human. We propose "TMCO1 defect syndrome" as the name of this condition.

Fig. 1.

Partial pedigree of the family with TMCO1 defect syndrome. Filled symbols represent affected individuals, and open symbols represent unaffected individuals. Circles and squares denote females and males, respectively. A double line identifies consanguinity. Arrows indicate affected individuals included in genetic mapping study and sequence analysis.

Fig. 2.

Clinical characteristics of TMCO1 defect syndrome. (A–G) Facial features of the syndrome (low hairline, brachycephaly, flat face, highly-arched bushy eyebrows, synophrys, long eyelashes, orbital hypertelorism, wide nose bridge, short nose with anterverted nares, microdontism, and generalized gingival hyperplasia) in six patients. Parental consent has been obtained for publication of these photographs. (H) Magnetic resonance imaging (MRI) of brain of a 3-month-old female, showing prominence of cerebrospinal fluid (CSF) space around the frontal lobes with extention into the anterior interhemisheric fissure. (I) Chest x-ray film of 4-day-old male showing multiple rib anomalies.

Fig. 3.

Genetic mapping of TMCO1 defect syndrome found in the Old Order Amish of northeastern Ohio. (A) Autozygosity mapping using Affymetrix GeneChip 10K SNP miroarrays and six affected individuals revealed homozygous haplotype identity for 17 SNPs on chromosome 1q23.3-q24.1. (B) Genotypes for 11 affected individuals from 3 separate Amish demes reveal that the TMCO1 mutation resides on two distinct SNP haplotypes. The original six patients are displayed first (black box, pink shading). The two Somerset County, PA, patients (next two columns, tan shading) share homozygous haplotype identity with the six original patients, whereas the three Lancaster County, PA, patients are identically homozygous for a distinct haplotype surrounding TMCO1 (yellow shading). In all, the 11 genotyped patients share homozygous genotypes at a mere three SNP loci spanning no more than 1.2 Mb. TMCO1 physically maps between rs952375 and rs1372685 (red letters).

Fig. 4.

Identification of the disease-causing mutation in TMCO1 gene. (A) Sequence electropherograms showing the homozygous c.139_140delAG mutation compared with a normal control. (B) Schematic of TMCO1 protein indicating position of identified mutation and protein structure. Protein structural regions are predicted by SMART. The transmembrane (TM1 and TM2) and coiled-coil domains are shown in green and blue, respectively. The three verified phosphoserine residues (S60, S184, and S188) are indicated by red stars.