1887

Abstract

A consanguineous family of Pakistani ethnicity with two female siblings (22 and 19 years of age), affected by a autosomal recessive Autism Spectrum Disease, was studied by homozygosity mapping and whole Exome Next Generation Sequencing [NGS] of the two affected siblings and one parent to identify the responsible gene and mutation. The disorder is marked by intellectual disability, speech and motor delay, congenital malformations and possibly autism spectrum disorder (ASD). The malformations include microcephaly, microphthalmia, micrognathia and arachnodactyly with hyperextensibility and persistent fetal pads in fingers and toes. The offending gene was mapped to five possible homozygous genomic regions [[6q, 12q, 17p, 20p, 22q], as the family structure did not allow identification of a single interval with a significant LOD score. Comparative analyses of the NGS data for autosomal recessive inheritance and data mining for damaging variants within the homozygosity intervals identified a damaging homozygous c.C1675T / p.R559C mutation in the MYO1A gene, at 12q13.3. The mutation co-segregates with the disease phenotype within the family, is absent in known polymorphism databases and in 400 ethnically matched control chromosomes. Myosins are molecular motors that, upon interaction with actin filaments, utilize energy from ATP hydrolysis to generate mechanical force. The N-terminal motor domain contains both ATP-binding and actin-binding sequences. Following the motor domain is a light-chain-binding 'neck' region containing 1-6 copies of a repeat element, the IQ motif that serves as a binding site for calmodulin and other members of the EF-hand superfamily of calcium-binding proteins. The C terminus has a distinct tail domain that serves in dimerization, membrane binding, protein binding, and/or enzymatic activities and targets each myosin to its particular subcellular location. Heterozygous mutations in MYO1A have been found in patients with sensorineural hearing loss, speculated to cause autosomal dominant sensorineural hearing loss but co-segregation to the phenotype has never been demonstrated. Two rare heterozygous MYO1A mutations [c.G2021A / p.G674D and one in the 3′UTR] have been found in patients with autism but their clinical significance is unknown. The association of MYO1A to autosomal recessive ASD without deafness in this family, elevates the importance of MYO1A both as causative and contributive gene for Autism Spectrum Disease

Loading

Article metrics loading...

/content/papers/10.5339/qfarc.2014.HBPP0434
2014-11-18
2019-11-22
Loading full text...

Full text loading...

http://instance.metastore.ingenta.com/content/papers/10.5339/qfarc.2014.HBPP0434
Loading
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error