Microcephaly and chorioretinopathy due to a homozygous <i>TUBGCP6</i> mutation.

<p>(<b>A</b>) An affected infant has marked microcephaly (>4SD below normal), a receding forehead, diminutive anterior fontanelle, and sutural ridging. She has cognitive delay and visual impairment but is socially engaged. (<b>B</b>) Head circumference and length plots for Mennonite microcephaly patients. (<b>C</b>) Brain magnetic resonance imaging (MRI) shows diffuse pachygyria, normal myelination, and (<b>D</b>) a hypoplastic cerebellar vermis.</p

Genetic mapping of seven Plain disorders.

<p>The results of autozygosity mapping using Affymetrix GeneChip 10 K or 50 K SNP microarrays are plotted for each disorder. The x-axis depicts chromosomal location on autosomes. Yellow peaks represent the number of contiguous homozygous SNPs shared by affected individuals and the purple peaks depict location scores. (<b>A</b>) Autozygosity mapping of two affected individuals identified a single, large block of homozygosity on chromosome 6 (yellow peak). Genotyping of 6 unaffected siblings excluded this homozygous block, but identified 12 genomic regions greater than 5 Mb in size (red peaks) that were consistent with linkage in the family. (<b>B</b>) List of genomic regions consistent with linkage in the single nuclear family with infantile parkinsonism-dystonia syndrome. Panels <b>C–H</b> provide mapping plots for the other 6 disorders. For two disorders (<b>C,D</b>), 50 K microarrays were used after 10 K microarrays failed to unequivocally localize the disease gene. The other four disorders (<b>E–H</b>) were mapped with 10 K microarrays.</p

Corticobasal degeneration in the brain of an infant who died from a homozygous <i>BRAT1</i> mutation.

<p>(<b>A</b>) Throughout frontal, occipital and temporal cortex, there is marked neuronal loss, gliosis with astrocytes (arrowheads) and swollen oligodendroglia. The arrow indicates a perivascular microcalcification (superior frontal gyrus, deep cortex, 10×). (<b>B</b>) The anterior hippocampus is smaller than expected and there is neuronal loss and gliosis in zone CA-1 (Sommer's sector), demarcated from the CA-2 sector by the dotted line (4×). (<b>C</b>) At 60× magnification, the putamen shows a paucity of neurons, abundant Alzheimer Type 2 astrocytes (arrowhead) and scattered microglial nodules (arrow). Heterologous overexpression of N-terminal FLAG-tagged human BRAT1 (<b>D</b>) and hBRAT1 c.638_639insA (<b>E</b>) in mouse IMCD3 cells. Wild-type Brat1 localizes to the nucleus and cytoplasm of mIMCD3 cells. Mutant Brat1 (c.638_639insA) does not localize to the nucleus and instead forms punctate aggregations in the cytoplasm. Similar results were obtained in hARPE-19 cells (data not shown). (<b>F</b>) RT-PCR demonstrating the stability of overexpressed human BRAT1 transcripts (∼2.6 kb) in hARPE-19 cells. A B-actin amplicon (∼450 bp) was used as a loading control on the same gel. (<b>G</b>) Western blot of lysates from human ARPE-19 cells transiently transfected with wt hBRAT1 displaying FLAG-hBRAT1 fusion protein at ∼90 kDa or with hBRAT1 c.638_639insA displaying the truncated FLAG-hBRAT1 mutant fusion protein at ∼44.5 kDa (FLAG-tag and linker = 3.1 kDa). B-actin was labeled as a loading control.</p

Overexpression of mouse HARS in mIMCD3 cells.

<p>(<b>A</b>) Wild-type N-terminal FLAG-HARS localizes to the cytoplasm. (<b>B</b>) Mutant N-terminal FLAG-HARS (p.Tyr454Ser) localizes to the cytoplasm in a manner that is indistinguishable from the wild-type localization shown in <b>A</b>. Transfected and non-transfected cells were labeled with anti-FLAG M2 monoclonal antibody and AlexaFluor 488-conjugated anti-mouse IgG₁ (green fluorescence). (<b>C</b>) Reaction velocity vs. human tRNA^His concentration for histidine aminoacylation of tRNA^His by wild-type murine HARS (HARS) and p.Tyr454Ser (Y454S) HARS. Scale bar = 10 µm in <b>A</b> and <b>B</b>.</p

Pathogenic Variant Summary.

<p>Pathogenic Variant Summary.</p

Genetic Mapping Summary.

<p>Genetic Mapping Summary.</p

Symptomatic epilepsy and skull dysplasia due to a homozygous <i>SNIP1</i> mutation.

<p>(<b>A</b>) Two affected brothers presented with severe psychomotor delay, intractable seizures, bulbous nose, wide mouth and tongue, broad jaw with protuberant angles, short hands, short tapered fingers, and broad thumbs. (<b>B,C</b>) Brain MRI (B, axial T2; C, coronal T1) MRI showed enlarged ventricles, a thin corpus callosum, hypomyelination, and an irregular, undulating skull surface. (<b>D</b>) Mouse FLAG-SNIP1 (wt) fusion protein, when transiently overexpressed in mIMCD3 cells, localizes to the nucleus in a punctate pattern consistent with transcriptional complexes. (<b>E</b>) Mouse FLAG-SNIP1 (p.Glu353Gly) localizes to the nucleus, but with a more aggregated distribution. (<b>F</b>) <i>Top</i> – Reverse-transcriptase PCR from three wild-type mSNIP1-transfected samples and four c.1058A>G mSNIP1-transfected samples. mSNIP1 amplicon – 400 bp. mGAPDH (loading control) – 1037 bp amplicon. <i>Bottom</i> – Western blot of lysates from mIMCD3 cells transiently transfected with wt (lanes wt_1&2) or c.1058A>G (lanes p.Glu353Gly_1&2) mSNIP1 displaying the FLAG-mSNIP fusion protein at ∼48 kDa. The 140-kDa non-specific band was used as a loading control. Data shown are two out of four replicate sets of transfections.</p