ISPD gene

isoprenoid synthase domain containing

The ISPD gene provides instructions for making a protein that is found in many of the body's tissues but is particularly abundant in the brain.

Although the function of the ISPD protein is unclear, researchers believe that it is involved in the modification of a protein called alpha (α)-dystroglycan. Specifically, ISPD is thought to aid in the addition of chains of sugar molecules to α-dystroglycan through a process known as glycosylation. Glycosylation is critical for the normal function of α-dystroglycan.

The α-dystroglycan protein helps anchor the structural framework inside each cell (cytoskeleton) to the lattice of proteins and other molecules outside the cell (extracellular matrix). In skeletal muscles, glycosylated α-dystroglycan helps stabilize and protect muscle fibers. In the brain, it helps direct the movement (migration) of nerve cells (neurons) during early development.

Genetics Home Reference provides information about limb-girdle muscular dystrophy.

Mutations in the ISPD gene cause Walker-Warburg syndrome, the most severe form of a group of disorders known as congenital muscular dystrophies. Walker-Warburg syndrome causes muscle weakness and abnormalities of the brain and eyes. Because of the severity of the problems caused by this condition, affected individuals usually do not survive past early childhood.

ISPD gene mutations involved in Walker-Warburg syndrome prevent the normal glycosylation of α-dystroglycan. As a result, α-dystroglycan can no longer effectively anchor cells to the proteins and other molecules that surround them. Without functional α-dystroglycan to stabilize muscle cells, muscle fibers become damaged as they repeatedly contract and relax with use. The damaged fibers weaken and die over time, which affects the development, structure, and function of skeletal muscles in people with Walker-Warburg syndrome.

Defective α-dystroglycan also affects the migration of neurons during the early development of the brain. Instead of stopping when they reach their intended destinations, some neurons migrate past the surface of the brain into the fluid-filled space that surrounds it. Researchers believe that this problem with neuronal migration causes a brain abnormality called cobblestone lissencephaly, in which the surface of the brain lacks the normal folds and grooves and instead appears bumpy and irregular. Less is known about the effects of ISPD gene mutations on other parts of the body.

Mutations in the ISPD gene have been found in individuals with a less severe form of muscular dystrophy known as limb-girdle muscular dystrophy. Individuals with this condition have muscle weakness in the arms and legs that begins in childhood; this weakness leads to difficulty walking. Some people with limb-girdle muscular dystrophy also have heart problems. As in Walker-Warburg syndrome (described above), ISPD gene mutations that cause limb-girdle muscular dystrophy prevent the normal glycosylation of α-dystroglycan. It is unclear how mutations in this gene cause a range of muscular dystrophies.

Cytogenetic Location: 7p21.2, which is the short (p) arm of chromosome 7 at position 21.2

Molecular Location: base pairs 16,087,527 to 16,422,562 on chromosome 7 (Homo sapiens Annotation Release 108, GRCh38.p7) (NCBI)

Cytogenetic Location: 7p21.2, which is the short (p) arm of chromosome 7 at position 21.2
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  • 4-diphosphocytidyl-2C-methyl-D-erythritol synthase homolog
  • hCG_1745121
  • isoprenoid synthase domain-containing protein
  • IspD
  • MDDGA7
  • Nip
  • notch1-induced protein