Mental Retardation, Autosomal Recessive 60

A number sign (#) is used with this entry because of evidence that autosomal recessive mental retardation-60 (MRT60) is caused by homozygous mutation in the TAF13 gene (600774) on chromosome 1p13.

Clinical Features

Tawamie et al. (2017) reported 4 patients from 2 unrelated consanguineous families with a neurodevelopmental disorder characterized by mild intellectual disability and poor overall growth with variable microcephaly. In the first family, of Syrian Kurdish descent, 2 sibs had low birth weight and showed delayed psychomotor development. At age 16 years, the older sib had severe overall poor growth with short stature (-6 SD), low weight (-9.39 SD), and microcephaly (-7 SD), as well as no signs of puberty and delayed bone age. The other sib had microcephaly (-5.83 SD) and low weight (-3.57 SD). Brain imaging of the younger sib at age 10 months showed delayed myelination and suspected pachygyria. In the second family, from southern Italy, 2 teenaged brothers also had low birth weight and mild microcephaly (-2 to -2.4 SD), but not as severe as in the first family. Each brother had a single febrile seizure and no dysmorphic features. Head CT scan of 1 patient was normal. Both patients had delayed bone age and showed delayed puberty. One brother was noted to attend normal school, but had learning and socialization difficulties.

Inheritance

The transmission pattern of MRT60 in the families reported by Tawamie et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 2 unrelated consanguineous families with MRT60, Tawamie et al. (2017) identified homozygous missense mutations in the TAF13 gene (M40K, 600774.0001 and L31H, 600774.0002). The mutations, which were found by a combination of homozygosity mapping and exome sequencing, were confirmed by Sanger sequencing. The mutations segregated with the disorder in both families. Transfection of the mutations into HeLa cells showed that both mutant TAF13 proteins had decreased interaction with TAF11 (600772), thus impairing formation of the functional heterodimer. The M40K mutation had a more deleterious effect than the L31H mutation, which was consistent with the more severe phenotype in the patients with the M40K mutation. Knockdown of the TAF13 gene using siRNA in human neuroblastoma cells resulted in transcriptional dysregulation of genes involved in movement, migration, proliferation, morphology, protrusion formation, and differentiation. These changes affected neuron development and proliferation as well as neuritogenesis. Neuronal cells with knockdown of TAF13 showed increased proliferation and altered differentiation compared to controls. The findings highlighted the role of TAF13 in neuronal development.