This report describes spinal muscular atrophy, lower extremity-predominant 2 (SMALED2), an autosomal dominant form of spinal muscular atrophy. The human gene implicated in this disease is BICD2, which encodes an adaptor protein linking the dynein motor complex to various cargos; it is also involved in Golgi dynamics. Heterozygous mutation in the BICD2 gene can also cause SMALED2B (MIM:618291), a more severe disorder.
There is a single orthologous gene in Drosophila, Dmel\BicD, for which many amorphic mutations, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. There is a second gene in human, BICD1, that is orthologous to Dmel\BicD.
The human BICD2 gene has not been introduced into flies.
Mutational lesions analogous to variants implicated in SMALED2 have been introduced into flies via UAS transgenic constructs of Dmel\BicD. Neuron-specific expression of the variant forms (but not wild-type) results in reduced neuromuscular junction size in larvae and impaired locomotion in adult flies. Expression in muscles has no obvious effect on motor function. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): S103L in the fly BicD gene (corresponds to S107L in the human BICD2 gene); T644M in the fly BicD@ gene (corresponds to T703M in the human BICD2 gene).
Females heterozygous for loss-of-function mutations of Dmel\BicD exhibit reduced fertility; homozygous females are sterile, producing embryos with a bicaudal phenotype (maternal-effect lethal). Many physical and genetic interactions of Dmel\BicD have been described; see below and in the BicD gene report.
[updated May 2020 by FlyBase; FBrf0222196]
Spinal muscular atrophy (SMA) is characterized by progressive muscle weakness resulting from degeneration and loss of the anterior horn cells (i.e., lower motor neurons) in the spinal cord and the brain stem nuclei. Onset ranges from before birth to adolescence or young adulthood. Poor weight gain, sleep difficulties, pneumonia, scoliosis, and joint contractures are common complications. [From GeneReviews, Spinal Muscular Atrophy, pubmed:20301526 2016.07.11]
[SPINAL MUSCULAR ATROPHY, LOWER EXTREMITY-PREDOMINANT, 2A, CHILDHOOD ONSET, AUTOSOMAL DOMINANT; SMALED2A](https://omim.org/entry/615290)
[BICD CARGO ADAPTOR 2; BICD2](https://omim.org/entry/609797)
Spinal muscular atrophy with lower extremity predominance (SMA-LED) is characterized by muscle weakness and wasting (atrophy) in the lower limbs, most severely affecting the thigh muscles (quadriceps). (In SMA-LED, the "D" stands for dominant.)[Genetics Home Reference, Spinal muscular atrophy with lower extremity predominance; 2018.10.02]
SMALED2 is an autosomal dominant form of spinal muscular atrophy characterized by early-childhood onset of muscle weakness and atrophy predominantly affecting the proximal and distal muscles of the lower extremity, although some patients may show upper extremity involvement. The disorder results in delayed walking, waddling gait, difficulty walking, and loss of distal reflexes. The disorder shows very slow progression throughout life (summary by Oates et al., 2013; pubmed:23664120). [from MIM:615290; 2018.10.02]
Lower extremity-predominant spinal muscular atrophy-2 (SMALED2) is caused by heterozygous mutation in the BICD2 gene. [from MIM:615290; 2018.10.02]
BICD2 encodes an adapter protein linking the dynein motor complex to various cargos, affecting minus-end-directed motility along microtubules. [Gene Cards, BICD2; 2018.10.02]
BICD2 is an evolutionarily conserved motor adaptor protein that is involved in dynein-mediated transport by linking the dynein motor complex to various cargoes (summary by Teuling et al., 2008; pubmed:18579581). BICD2 is also involved in Golgi dynamics and vesicular and mRNA transport and interacts with multiple proteins involved in intracellular transport (summary by Neveling et al., 2013; pubmed:23664116). [from MIM:609797; 2018.10.02]
Many to one: 2 human to 1 fly; the human genes are BICD2 and BICD1.
Moderate- to high-scoring ortholog of human BICD2 and BICD1 (1 Drosophila to 2 human). Dmel\BicD shares 39% identity and 57-58% similarity with the human genes.
