( From OMIM) A missense mutation in the DPP6 gene (M385L; 126141.0002) was identified in a family segregating microcephaly and autosomal dominant mental retardation. Also in a 12-year-old boy (BY0712) and a 15-year-old girl (BY2018) with microcephaly and mental retardation (MRD33; 616311), Liao et al. (2013) identified a de novo heterozygous 336 and 362 kb deletion covering only the DPP6 gene. In mice, knockdown of Dpp6 using short hairpin RNA (shRNA) resulted in smaller brains and learning disabilities compared to wildtype littermates.
Encephalitis due to antibodies targeting dipeptidyl-peptidase-like protein 6 (DPPX), a potassium channel subunit, is rare. The illness is typically characterized by a triad of weight loss, CNS hyperexcitability and cognitive symptoms, but recent reports suggest that the clinical picture may be more heterogeneous. Here, we describe the case of a 63-year-old female who was admitted to the hospital with severe extremity pain, which had been preceded by diarrhea and weight loss. She later developed cognitive changes, and her general condition rapidly deteriorated. Extensive workup did not reveal gastrointestinal illness or underlying malignancies. MRI of the brain was normal. Analyses of blood and cerebrospinal fluid showed normal cell counts but high titres of DPPX antibodies in blood and cerebrospinal fluid. The patient was treated with intravenous methylprednisolone followed by rituximab. At 1-year follow-up, she was without pain and had completely recovered. In this case, DPPX-associated autoimmune encephalitis was dominated by severe extremity pain, illustrating that sensory symptoms may be one of the main complaints in these patients. It is important for clinicians to be aware of the heterogeneous clinical picture in this serious condition, since correct diagnosis and treatment with immunosuppressants are associated with favorable prognosis.
Title: Loss-of-function variation in the DPP6 gene is associated with autosomal dominant microcephaly and mental retardation Liao C, Fu F, Li R, Yang WQ, Liao HY, Yan JR, Li J, Li SY, Yang X, Li DZ Ref: Eur Journal of Medical Genetics, 56:484, 2013 : PubMed
The molecular basis of autosomal dominant microcephaly, a disorder associated with small head circumferences that results in variable mental retardation, is largely unknown. In the present study, we conducted a variation analysis of the DPP6 gene in patients with autosomal dominant microcephaly and variable mental retardation. The copy number variation analysis of DPP6 was performed on DNA samples from 22 patients with microcephaly using high-resolution, array-based genomic hybridization, and sequence analysis was performed to screen mutations in another 50 microcephalic patients. Two de novo deletions and one missense mutation in familial microcephalic patients were identified. The transfection of plasmids encoding green fluorescent protein-pLLU2G-shDPP6 fusion proteins in mouse brains revealed that the decreased expression of the DPP6 gene slightly reduced the weight of the mouse brains and resulted in mouse learning disabilities compared with their wild-type littermates. Our data indicate that the loss-of-function variations in DPP6 are associated with autosomal dominant microcephaly and mental retardation. DPP6 appears to play a major role in the regulation of proliferation and migration of neurons in neurogenesis, most likely by participating in neuronal electrical excitability, synaptic integration, and plasticity.
