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1.  Familial 6p22.2 Duplication Associates with Mild Developmental Delay and Increased SSADH Activity 
We present a family with mild developmental delay and a duplication (6)(p22.2). Array CGH analyses revealed this 0.7 Mb duplication in all three patients, spanning candidate genes ALDH5A1, DCDC2 and KIAA0319. Results were confirmed by MLPA analysis of the dyslexia genes DCDC2 and KIAA0319. Of interest, ALDH5A1 encodes succinate semialdehyde dehydrogenase (SSADH), an enzyme responsible for γ-amino-butyric acid (GABA) degradation. Inherited deficiency of SSADH results in accumulation of the neuromodulator γ-hydroxybutyrate (GHB), which likely contributes to some aspects of the neurological phenotype of SSADH deficiency (MIM #271980). Based upon autosomal-recessive inheritance, we sequenced ALDH5A1 in all patients, which revealed no pathogenic mutations. SSADH enzyme studies in cultured white cells confirmed elevated SSADH activity, consistent with the duplication, whereas concentrations of SSA were slightly elevated in urine, suggesting oxidant stress. We speculate that the duplication (6)(p22.2) and corresponding hyperactive level of SSADH activity may have negative consequences for GABA metabolism and the role of SSADH in other metabolic sequences.
PMCID: PMC3082589  PMID: 21438145
duplication 6p22.2; SSADH; mild mental retardation
2.  9q22 Deletion - First Familial Case 
Only 29 cases of constitutional 9q22 deletions have been published and all have been sporadic. Most associate with Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS, MIM #109400) due to haploinsufficiency of the PTCH1 gene (MIM *601309).
Methods and Results
We report two mentally retarded female siblings and their cognitively normal father, all carrying a similar 5.3 Mb microdeletion at 9q22.2q22.32, detected by array CGH (244 K). The deletion does not involve the PTCH1 gene, but instead 30 other gene,s including the ROR2 gene (MIM *602337) which causing both brachydactyly type 1 (MIM #113000) and Robinow syndrome (MIM #268310), and the immunologically active SYK gene (MIM *600085). The deletion in the father was de novo and FISH analysis of blood lymphocytes did not suggest mosaicism. All three patients share similar mild dysmorphic features with downslanting palpebral fissures, narrow, high bridged nose with small nares, long, deeply grooved philtrum, ears with broad helix and uplifted lobuli, and small toenails. All have significant dysarthria and suffer from continuous middle ear and upper respiratory infections. The father also has a funnel chest and unilateral hypoplastic kidney but the daughters have no malformations.
This is the first report of a familial constitutional 9q22 deletion and the first deletion studied by array-CGH which does not involve the PTCH1 gene. The phenotype and penetrance are variable and the deletion found in the cognitively normal normal father poses a challenge in genetic counseling.
PMCID: PMC3135502  PMID: 21693067
4.  Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy  
The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1–NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are “ciliopathies”. Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.
PMCID: PMC2827951  PMID: 20179356
5.  Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease 
Nature genetics  2008;40(2):155-157.
The most severe forms of motoneuron disease manifest in utero are characterized by marked atrophy of spinal cord motoneurons and fetal immobility. Here, we report that the defective gene underlying lethal motoneuron syndrome LCCS1 is the mRNA export mediator GLE1. Our finding of mutated GLE1 exposes a common pathway connecting the genes implicated in LCCS1, LCCS2 and LCCS3 and elucidates mRNA processing as a critical molecular mechanism in motoneuron development and maturation.
PMCID: PMC2684619  PMID: 18204449

Results 1-5 (5)