Gabriela Rudd Garces, Anna Letko, Irene M. Häfliger, Jana Müller, Christiane Herden, Anne Nesseler, Henrik Wagner, Martin J. Schmidt, Cord Drögemüller, Gesine Lühken
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MFSD2A frameshift variant in Kerry Hill sheep with microcephaly
Microcephaly is a rare neurodevelopmental disorder characterized by reduced skull circumference and brain volume that occurs sporadically in farm animals. We investigated an early-onset neurodegenerative disorder observed in seven lambs of purebred Kerry Hill sheep. Clinical signs included inability to stand or severe ataxia, convulsions, and early death. Diagnostic imaging and brain necropsy confirmed microcephaly. The pedigree of the lambs suggested monogenic autosomal recessive inheritance. We sequenced the genome of one affected lamb, and comparison with 115 control genomes revealed a single private protein-changing variant. This frameshift variant, MFSD2A: c.285dupA, p.(Asp96fs*9), represents a 1-bp duplication predicted to truncate 80% of the open reading frame. MFSD2A is a transmembrane protein that is essential for maintaining blood–brain barrier homeostasis and plays a key role in regulating brain lipogenesis. Human MFSD2A pathogenic variants are associated with a neurodevelopmental disorder with progressive microcephaly, spasticity, and brain imaging abnormalities (NEDMISBA, OMIM 616486). Here we present evidence for the occurrence of a recessively inherited form of microcephaly in sheep due to a loss-of-function variant in MFSD2A (OMIA 002371-9940). To the best of our knowledge, this is the first report of a spontaneous MFSD2A variant in domestic animals.
期刊介绍:
Animal Genetics reports frontline research on immunogenetics, molecular genetics and functional genomics of economically important and domesticated animals. Publications include the study of variability at gene and protein levels, mapping of genes, traits and QTLs, associations between genes and traits, genetic diversity, and characterization of gene or protein expression and control related to phenotypic or genetic variation.
The journal publishes full-length articles, short communications and brief notes, as well as commissioned and submitted mini-reviews on issues of interest to Animal Genetics readers.