The Baker Laboratory focuses on identifying the causes of birth defects or diseases of the urogenital tract.
Some of them include:
- Disorders of Sexual Development
- Prune Belly Syndrome
- Female reproductive anomalies
- Hypospadias
- Pediatric kidney stones
Our ultimate goal is to design better treatments for these conditions.
The Baker Laboratory focuses on identifying the causes of birth defects or diseases of the urogenital tract, particularly:
- Disorders of sexual development
- Prune belly syndrome
- Female reproductive anomalies
- Hypospadias
- Pediatric kidney stones
Our ultimate goal is to design better treatments for these conditions.
Past genetic testing has not revealed genetic components to many urogenital diseases – in fact, test results often appear to be normal. However, we believe that with new genetic tests, which are much more powerful and have higher resolution, it's worthwhile to search again for underlying genetic problems.
Dr. Baker discusses her lab's research in pediatric urology research.
This research requires a stepwise approach:
- We need patients and their families to participate in our research. Most studies involve only an office visit and a small blood sample. There is no cost to participate.
- Using ‘next-generation sequencing’ and comparative genomic hybridization DNA tests, we attempt to identify the genes and their clinical human mutations responsible for these disorders.
- We use biochemical and cell-biology methods, and create models, to study the gene and the mutation further to show that it is functionally impaired.
- We see if we can correct or improve the genetic problem with therapies designed specifically for the disorder.
Standard genetic testing, including karyotyping or Sanger DNA sequencing, has failed to detect chromosomal abnormalities in many urogenital anomalies. However, karyotyping can only detect large chromosomal alterations (changes affecting >5 Mb of DNA), and often misses microdeletions or microduplications.
New molecular techniques can overcome these limitations and comprehensively assay the entire human genome. These newer techniques, including high-resolution comparative genomic hybridization and whole exome sequencing, have great potential to identify the molecular basis of many unknown urogenital congenital defects.
In the nucleus of our cells, our genetic code is packaged in 48 chromosomes, composed of long strands of DNA that carry our genes. Sometimes mutations or other DNA changes occur which can cause disease or birth defects. New DNA tests can find these problems at much greater detail and speed than in the past. Disorders of sexual development (DSD) are a group of varied conditions, all of which involve alterations in embryonic development and/or sex hormones. These anomalies cause mismatches between the blood karyotype, the gonads, and the internal and/or external genitalia.
Internal and external genitalia are masculinized or feminized by critically-timed activation of genes and hormones. These factors trigger the gonad to mature into either an ovary, testis, undifferentiated gonad, streak gonad, dysgenetic gonad, or ovotestis.
A normal embryonic testis makes sex hormones (insulin-3, testosterone, and Müllerian inhibiting substance) that act on the hormonally responsive internal and external genitalia to cause them to masculinize. In contrast, a normal embryonic ovary does not make these sex hormones, leading to feminization of the internal and external genitalia.
In many DSD cases, we can perform DNA tests and find the cause. However, some DSD cases remain unsolved. By studying the unsolved cases or affected families, we hope to discover unknown genes regulating sexual development.
Inheritance pattern of a genitourinary birth defect over five generations of a family. Hypospadias is one of the most common human birth defects, affecting 1 out of every 125 newborn males. The urine tube inside of the penis, the urethra, does not form correctly. The opening for the urine (the urethral meatus or 'pee-hole') is not at the end of the penis but instead is on the underside of the penis, on the shaft, or in the scrotum.
In some patients, hypospadias is caused by abnormal androgen stimulation or abnormal androgen metabolism, but for the majority of patients, the cause is unknown. Currently, surgery is the only way to correct hypospadias.
In 15 percent of cases, hypospadias affects more than one male in the family, suggesting that it is an inherited problem. While some hypospadias genes are known, in some affected families we do not know the cause. We hope to enroll more families with hypospadias and use new next-generation DNA technologies to identify unknown hypospadias genes.
Urinary stones (urolithiasis) can affect children of any age. About 80 percent of stones in children are calcium oxalate stones. In 60 percent of pediatric cases, urolithiasis runs in the family, often affecting several generations. The family histories suggest a genetic cause, with dominant inheritance, but the gene(s) involved are not known.
We are very interested in identifying new causes of pediatric calcium oxalate urolithiasis and invite families to participate in our research. Large families are extremely helpful for studies using next-generation DNA technologies.
We continue to seek study participants to find new causes for this condition.
A 13-year-old hypercalciuric girl with kidney stones (two on the left and 16 on the right). She had hematuria and chronic back pain for two years before diagnosis, despite multiple physician visits. The overall goal of this project is to identify the cause of Prune Belly Syndrome (PBS), a multi-system congenital human urologic anomaly. We are taking a personalized-medicine approach to identify the molecular cause of this rare but severe disorder.
A child with prune belly syndrome
The hallmark features of PBS include the triad of, 1) hypoplastic or absent abdominal wall skeletal musculature, 2) bladder smooth muscle dysplasia leading to urinary tract dilation with megacystis and refluxing ureters, and 3) bilateral undescended testes.
Its morbidity and mortality are devastating: 20 percent of babies are stillborn, 43 percent are born prematurely, and 30 percent die of renal failure or urosepsis by age 2. PBS most frequently affects boys.
Our NIH-funded study has worked extensively with the Prune Belly Syndrome Network (PBSN), the largest US family support group for PBS. With the help of this organization, more than 300 people from more than 100 families have provided us with medical information and DNA samples. Several families have had more than one child with PBS; these families are called multiplex PBS kindreds, and they are especially helpful in accelerating the pace of discovery.
In some kindreds, the inheritance pattern supports a sex-limited autosomal recessive or X-linked inheritance. Recently, several genes have been implicated in PBS, but the overwhelming majority of PBS patients do not carry genomic variants in these genes. Thus, additional PBS-causing genes remain unknown.
We are using Next Generation Sequencing to identify genes that cause PBS, and we are studying the functional impact of clinical mutations in these genes. Using whole-exome DNA sequencing, we have identified candidate PBS genes with mutations. One especially interesting mutation found in two brothers with PBS affects muscle cells. We are further testing the mutation to unravel how it causes PBS.
More individuals and multiplex families with PBS are needed for this study.