Mental Retardation, Autosomal Recessive 39

A number sign (#) is used with this entry because autosomal recessive mental retardation-39 (MRT39) is caused by homozygous mutation in the TTI2 gene (614426) on chromosome 8p12.

Clinical Features

Langouet et al. (2013) reported 3 sibs, born of consanguineous Algerian parents, with mental retardation and behavioral problems. All had a normal neonatal period, but showed delayed psychomotor development and severe speech delay. Examination at ages 30 to 36 years revealed microcephaly (-3 to -4 SD), short stature, kyphoscoliosis, and dysmorphic facial features, including sloping forehead, deep-set eyes, synophrys, prominent nose, anteverted large ears, and dental anomalies. Behavioral abnormalities included hyperactivity, aggression, and stereotypic movements. Seizures were not reported. Laboratory analysis showed mild lymphopenia of naive T cells, but increased susceptibility to infection was not reported.

Inheritance

The transmission pattern in the family with mental retardation reported by Langouet et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arabic) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family M100, they identified homozygosity for a missense mutation in the TTI2 gene (P367L; 614426.0001) in 4 sibs with moderate nonsyndromic mental retardation. The parents were first cousins and had 4 healthy children.

In 3 sibs, born of consanguineous Algerian parents, with mental retardation and dysmorphic features, Langouet et al. (2013) identified a homozygous missense mutation in the TTI2 gene (I436N; 614426.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed almost undetectable levels of mutant TTI2 compared to controls, although mRNA levels were normal. Patient cells also showed decreased levels of the other 2 components of the Triple T complex (TTI1, 614425 and TELO2, 611140), indicating impaired stability of the complex, as well as decreased amounts of ATM (607585), PRKDC (600899), and MTOR (601231) (less than 50% of controls for all 3 proteins).